Analysis Tools
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• patchy interstitial mononuclear infiltration is observed at day 10, but resolves by 3 weeks; no myocyte hypertrophy is observed
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• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
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• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing
• marked transient systolic and diastolic depression occurs, with full recovery observed by 3 weeks after stopping tamoxifen treatment
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• patchy interstitial mononuclear infiltration is observed at day 10, but resolves by 3 weeks; no myocyte hypertrophy is observed
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• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
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• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing
• marked transient systolic and diastolic depression occurs, with full recovery observed by 3 weeks after stopping tamoxifen treatment
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• at 4-6 weeks after tamoxifen treatment, ex vivo perfused working hearts show a significant reduction in myocardial triacylglycerol (TAG) content relative to control hearts
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• following ischemia/reperfusion, ex vivo perfused working hearts from tamoxifen-treated mice display significantly improved myocardial functional recovery relative to control hearts, as shown by increased heart rate peak systolic pressure (HR PSP) and cardiac power compared to the pre-ischemic phase
• improved recovery is associated with lower calculated proton production prior to and following ischemia relative to control hearts
• during reperfusion, ATP production relative to cardiac work is dramatically reduced and myocardial lactate levels are significantly decreased, indicating increased post-ischemic cardiac efficiency relative to control hearts
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• at 4-6 weeks after tamoxifen treatment, ex vivo perfused working hearts show a 48% reduction in FA (palmitate) oxidation rates relative to control hearts
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• at 4-6 weeks after tamoxifen treatment, ex vivo perfused working hearts show a 68% increase in glucose oxidation rates, with no significant change in glycolytic rates relative to control hearts
• despite switch to increased mitochondrial oxidation of glucose versus FAs (53% of TCA cycle acetyl-CoA production versus 26% in controls), total TCA cycle acetyl-CoA production and total ATP production via exogenously supplied substrates are not significantly altered
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• at 4-6 weeks after tamoxifen treatment, ex vivo perfused working hearts display significantly decreased fatty acid (palmitate) uptake relative to control hearts
• however, serum concentrations of free FAs are not significantly altered
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• at 4-6 weeks after tamoxifen treatment, ex vivo perfused working hearts show a significant reduction in myocardial triacylglycerol (TAG) content relative to control hearts
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| N |
• at 4-6 weeks after tamoxifen treatment, H&E staining showed normal cardiomyocyte morphology in apical heart sections
• ex vivo perfused working hearts show normal heart rate (HR), HR peak systolic pressure (PSP), cardiac power, cardiac output and coronary flow rates, as well as normal myocardial ATP, ADP, AMP, and phosphocreatine levels during aerobic perfusions
• in vivo, tamoxifen-treated hearts show normal baseline cardiac function with no detectable structural or morphological abnormalities
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• at 4-6 weeks after tamoxifen treatment, ex vivo perfused working hearts show a significant reduction in myocardial triacylglycerol (TAG) content relative to control hearts
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• following ischemia/reperfusion, ex vivo perfused working hearts from tamoxifen-treated mice display significantly improved myocardial functional recovery relative to control hearts, as shown by increased heart rate peak systolic pressure (HR PSP) and cardiac power compared to the pre-ischemic phase
• improved recovery is associated with lower calculated proton production prior to and following ischemia relative to control hearts
• during reperfusion, ATP production relative to cardiac work is dramatically reduced and myocardial lactate levels are significantly decreased, indicating increased post-ischemic cardiac efficiency relative to control hearts
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• at 4-6 weeks after tamoxifen treatment, ex vivo perfused working hearts show a 48% reduction in FA (palmitate) oxidation rates relative to control hearts
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• tamoxifen-treated mice do not show overt cardiac phenotypes, even 36 weeks after induction
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• significantly reduced viability at 8 weeks after tamoxifen treatment
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• after tamoxifen treatment
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• after tamoxifen treatment
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• increased cross-sectional area without change in length in tamoxifen-treated mice
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• in tamoxifen-treated mice
• however, overexpression of a phosphorylation-mimic mutant of NEXN (S437E) rescues cardiac hypertrophy
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• in tamoxifen-treated mice
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• in tamoxifen-treated mice
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• in tamoxifen-treated mice
• however, overexpression of a phosphorylation-mimic mutant of NEXN (S437E) rescues fibrosis
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• rapid onset in tamoxifen-treated mice with decreased left ventricular internal diameter, diastole, and a significant decrease in the left ventricular ejection fraction
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• in tamoxifen-treated mice
• however, overexpression of a phosphorylation-mimic mutant of NEXN (S437E) rescues cardiac hypertrophy
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• in tamoxifen-treated mice
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• in tamoxifen-treated mice
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• increased cross-sectional area without change in length in tamoxifen-treated mice
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• in tamoxifen-treated mice
• however, overexpression of a phosphorylation-mimic mutant of NEXN (S437E) rescues cardiac hypertrophy
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• disrupted integrity ruptured myofilaments, blurred Z-disk, and mitochondrial abnormalities in cardiomyocytes of tamoxifen-treated mice
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• in cardiomyocytes of tamoxifen-treated mice
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• in tamoxifen-treated mice
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• in tamoxifen-treated mice
• however, overexpression of a phosphorylation-mimic mutant of NEXN (S437E) rescues fibrosis
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice treated with tamoxifen at 6-8 weeks of age exhibit ventricular dilation, measured as an increase in end-diastolic and end-systolic volume, within 1-week post-induction
• cardiac chamber enlargement is transitory and recovers to pre-induction levels within 2 months
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• tamoxifen treated mice show a decrease in left ventricular ejection fraction within 1-week post-induction
• the reduced pump function is transitory and recovers to pre-induction levels within 2 months
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• echocardiography shows an increase in end-diastolic and end-systolic volume and decreased left ventricular ejection fraction within 1-week post-tamoxifen induction
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• tamoxifen-treated mice show increased fumarate and malate and the glycolytic metabolite glucose-6-phosophate in the myocardium
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• tamoxifen treated mice show a decrease in left ventricular ejection fraction within 1-week post-induction
• the reduced pump function is transitory and recovers to pre-induction levels within 2 months
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 2 weeks after tamoxifen-treatment, the total number of cardiomyocytes and percentage of mononucleated cardiomyocytes compared with control mice
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• 2 weeks after tamoxifen-treatment
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• 2 weeks after tamoxifen-treatment
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• increased heart weight to tibia length ratio 2 weeks after tamoxifen treatment
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• cardiomyocytes reenter the cell cycle 8 days after tamoxifen treatment
• increased cardiomyocytes proliferation in tamoxifen treated mice following induction of myocardial infarction
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• following induced myocardial infarction, tamoxifen-treated mice exhibit reduced fibrotic scarring with increased myocardial tissue compared with control mice
• however, mice exhibit ventricular dilation and reduced fractional shortening and ejection fraction 3 weeks after injury
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• 8 days after tamoxifen treatment
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• following induced myocardial infarction, tamoxifen-treated mice exhibit reduced fibrotic scarring with increased myocardial tissue compared with control mice
• however, mice exhibit ventricular dilation and reduced fractional shortening and ejection fraction 3 weeks after injury
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• 2 weeks after tamoxifen-treatment, the total number of cardiomyocytes and percentage of mononucleated cardiomyocytes compared with control mice
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• 2 weeks after tamoxifen-treatment
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• 2 weeks after tamoxifen-treatment
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• 8 days after tamoxifen treatment
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• increased heart weight to tibia length ratio 2 weeks after tamoxifen treatment
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• gross cardiac morphology is normal 8 weeks after tamoxifen treatment
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• at 20 weeks in tamoxifen-treated mice
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• myocyte disarray in tamoxifen-treated mice 12 weeks after transaortic constriction
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• increased posterior wall thickness in diastole after 20 weeks of tamoxifen treatment
• increased left ventricle internal dimension in tamoxifen-treated mice after transaortic constriction
• however, internal dimension is normal after 20 weeks of tamoxifen treatment
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• in tamoxifen-treated mice 12 weeks after transaortic constriction
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• highly variable focal and diffuse 20 weeks after tamoxifen treatment
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• decreased ejection fraction and isovolumic relaxation time in tamoxifen-treated mice
• reduced fractional shortening in tamoxifen-treated mice after transaortic constriction
• however, tamoxifen-treated mice exhibit normal left ventricle posterior wall thickness and left ventricle internal diameter
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• following transaortic constriction, tamoxifen-treated mice exhibit increased left ventricle internal dimension and reduced fractional shortening compared with control mice
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• following transaortic constriction, tamoxifen-treated mice exhibit increased left ventricle internal dimension and reduced fractional shortening compared with control mice
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• at 20 weeks in tamoxifen-treated mice
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• myocyte disarray in tamoxifen-treated mice 12 weeks after transaortic constriction
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• decreased ejection fraction and isovolumic relaxation time in tamoxifen-treated mice
• reduced fractional shortening in tamoxifen-treated mice after transaortic constriction
• however, tamoxifen-treated mice exhibit normal left ventricle posterior wall thickness and left ventricle internal diameter
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• highly variable focal and diffuse 20 weeks after tamoxifen treatment
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• all mice die 8 to 10 weeks after tamoxifen injection due to rapid progression to heart failure; mice appear sick and become inactive a few days before death
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• following tamoxifen treatment, hearts show an irregular alignment of cardiomyocytes, with frequent gaps between cells
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• amount of polymerized F-actin in cardiomyocytes progressively decreases after tamoxifen treatment
• myofibrils at the intercalated disks are often stretched and fragmented following tamoxifen treatment
• Z disks of cardiomyocytes are misaligned and myofibrils are split 60 days after tamoxifen treatment
• 60 days after tamoxifen treatment, cardiac tissue shows a lower density of myofibrils and a defect in demarcation of Z lines and M lines
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• 95% of intercalated disks of hearts are enlarged, irregularly shaped, and are thicker 60 days after tamoxifen treatment
• intercalated disks show extensive interdigitation and the presence of lacunae, a widened space at the site of myofibril attachment to the intercalated disks, following tamoxifen treatment
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• hearts show features of eccentric hypertrophy 2 months after tamoxifen treatment, with dilation of the ventricular chambers
• however, no concentric hypertrophy is seen
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• mild left ventricle enlargement is seen 1 month after tamoxifen treatment, without significant left atrium remodeling and moderately increased left ventricle mass index
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• dilation of the ventricular chambers is seen 2 months after tamoxifen treatment
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• mild fibrosis in subendocardial regions are seen 2 months after tamoxifen treatment
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• hearts are enlarged 2 months after tamoxifen treatment, with impaired contractility and relaxation
• however, thickening of the free wall is not seen
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• decrease in left ventricular contractility is seen 21 days after tamoxifen treatment, with a decrease in ejection fraction and mean shortening velocity of circumferential fibers
• contractility and relaxation are moderately altered at 1 month after tamoxifen treatment, however 2 months after tamoxifen treatment, a massive decrease in left ventricle contractility and relaxation are seen, with increased E/Ea ratio, indicating heart failure
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• contractility and relaxation are moderately altered at 1 month after tamoxifen treatment, however 2 months after tamoxifen treatment, a massive decrease in left ventricle contractility and relaxation are seen, with increased E/Ea ratio, indicating heart failure
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• heart failure is seen 8 to 10 weeks after tamoxifen treatment
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• following tamoxifen treatment, hearts show an irregular alignment of cardiomyocytes, with frequent gaps between cells
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• amount of polymerized F-actin in cardiomyocytes progressively decreases after tamoxifen treatment
• myofibrils at the intercalated disks are often stretched and fragmented following tamoxifen treatment
• Z disks of cardiomyocytes are misaligned and myofibrils are split 60 days after tamoxifen treatment
• 60 days after tamoxifen treatment, cardiac tissue shows a lower density of myofibrils and a defect in demarcation of Z lines and M lines
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• 95% of intercalated disks of hearts are enlarged, irregularly shaped, and are thicker 60 days after tamoxifen treatment
• intercalated disks show extensive interdigitation and the presence of lacunae, a widened space at the site of myofibril attachment to the intercalated disks, following tamoxifen treatment
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• hearts are enlarged 2 months after tamoxifen treatment, with impaired contractility and relaxation
• however, thickening of the free wall is not seen
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• decrease in left ventricular contractility is seen 21 days after tamoxifen treatment, with a decrease in ejection fraction and mean shortening velocity of circumferential fibers
• contractility and relaxation are moderately altered at 1 month after tamoxifen treatment, however 2 months after tamoxifen treatment, a massive decrease in left ventricle contractility and relaxation are seen, with increased E/Ea ratio, indicating heart failure
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• contractility and relaxation are moderately altered at 1 month after tamoxifen treatment, however 2 months after tamoxifen treatment, a massive decrease in left ventricle contractility and relaxation are seen, with increased E/Ea ratio, indicating heart failure
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• Z disks of cardiomyocytes are misaligned 60 days after tamoxifen treatment
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• hearts show features of eccentric hypertrophy 2 months after tamoxifen treatment, with dilation of the ventricular chambers
• however, no concentric hypertrophy is seen
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| dilated cardiomyopathy | DOID:12930 |
OMIM:PS115200 |
J:135043 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice treated with tamoxifen at 3 months develop lethal heart failure
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• mice treated with tamoxifen at 3 months develop lethal heart failure
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• tamoxifen-treated mice do not exhibit myocardial disarray or necrosis
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• 4 and 7 weeks after tamoxifen treatment, left atrial diameter is increased compared to in Atp2a2tm1.1Iemr homozygotes
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• after tamoxifen treatment
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• after tamoxifen treatment
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• tamoxifen-treated mice exhibit an increase in the time constant of isovolumetric pressure decay compared with Atp2a2tm1.1Iemr homozygotes
• 7 weeks after tamoxifen treatment, mice exhibit diastolic dysfunction compared with Atp2a2tm1.1Iemr homozygotes
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• 4 and 7 weeks after tamoxifen treatment
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• 4 weeks after tamoxifen treatment, mice exhibit reduced contractile function compared with Atp2a2tm1.1Iemr homozygotes as determined by Doppler imaging
• at low stimulation frequency, cardiomyocytes from tamoxifen-treated mice exhibit reduced contraction magnitude compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• 7 weeks after tamoxifen treatment, fractional shortening is reduced compared to in Atp2a2tm1.1Iemr homozygotes
• 4 and 7 weeks after tamoxifen treatment, end-diastolic pressure compared to in Atp2a2tm1.1Iemr homozygotes
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• 4 and 7 weeks after tamoxifen treatment, mice exhibit reduced maximum positive and minimum derivatives of the left ventricular pressure compared with Atp2a2tm1.1Iemr homozygotes
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• 4 and 7 weeks after tamoxifen treatment, anesthetized mice exhibit decreased heart rate compared with Atp2a2tm1.1Iemr homozygotes
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• cardiomyocytes from tamoxifen-treated mice exhibit reduced magnitude of calcium ion transients and prolonged time to half decay of calcium ion transients compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• when stimulated at a 6 Hz frequency, cardiomyocytes from tamoxifen-treated mice exhibit shorter diastolic sarcomere length and a greater increase in the contractile response per unit during systole compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• during the slow decline of caffeine transients in the presence of nickel ions, cardiomyocytes from tamoxifen-treated mice exhibit shorter sarcomere length compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• 4 weeks after tamoxifen treatment, cardiomyocytes exhibit reduced sarcoplasmic reticulum calcium ion content compared with cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• 7 weeks after treatment with tamoxifen, mice exhibit reduced maximal rate of cardiomyocyte relaxation compared with Atp2a2tm1.1Iemr homozygotes
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• 7 weeks after tamoxifen treatment
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• in tamoxifen-treated mice at 4 and 7 weeks
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• 4 weeks after tamoxifen treatment, mice exhibit reduced contractile function compared with Atp2a2tm1.1Iemr homozygotes as determined by Doppler imaging
• at low stimulation frequency, cardiomyocytes from tamoxifen-treated mice exhibit reduced contraction magnitude compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• 7 weeks after tamoxifen treatment, fractional shortening is reduced compared to in Atp2a2tm1.1Iemr homozygotes
• 4 and 7 weeks after tamoxifen treatment, end-diastolic pressure compared to in Atp2a2tm1.1Iemr homozygotes
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• after tamoxifen treatment
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• tamoxifen-treated mice survive until P40
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• not as severe as in mice Cnot3tm2.1Tya A1cfTg(Myh6-cre/Esr1*)1Jmk mice
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• not as severe as in mice Cnot3tm2.1Tya A1cfTg(Myh6-cre/Esr1*)1Jmk mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• as in mice with one copy of A1cfTg(Myh6-cre/Esr1*)1Jmk
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• as in mice with one copy of A1cfTg(Myh6-cre/Esr1*)1Jmk
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
The Med1tm2Jkr/Med1tm2Jkr A1cfTg(Myh6-cre/Esr1*)1Jmk/A1cf+ mouse heart is flaccid and flabby after tamoxifen induction.
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• mice survive between 13 and 28 days after the first day of tamoxifen injection
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• hearts appear increasingly flaccid by 14 days after first tamoxifen injection
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• mice treated with tamoxifen at 7 weeks of age exhibit an increase in heart size by 14 days after first tamoxifen injection
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• tamoxifen treated mice show thinning of the ventricular walls
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• tamoxifen treated mice show dilatation of the right and left ventricular chambers with thinning of the walls and myocardial cells
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• interstitial myocardial fibrosis in tamoxifen-treated hearts
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• tamoxifen-treated mice show diminished heart contractility with ejection fraction only 11% vs. 64% in controls and fractional shortening of 4.77% vs. 33.88% in controls
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• echocardiography indicates increased left ventricular end-diastolic internal dimension, and decreased fractional shortening and ejection fraction in tamoxifen treated mice
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• in tamoxifen treated mice
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• interstitial myocardial fibrosis in tamoxifen-treated hearts
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• tamoxifen-treated hearts show enhanced apoptosis, with the number of apoptotic cardiomyocytes increased about 10-fold
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• tamoxifen-treated mice show diminished heart contractility with ejection fraction only 11% vs. 64% in controls and fractional shortening of 4.77% vs. 33.88% in controls
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• tamoxifen-treated hearts show enhanced apoptosis, with the number of apoptotic cardiomyocytes increased about 10-fold
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• mice treated with tamoxifen at 7 weeks of age exhibit an increase in heart size by 14 days after first tamoxifen injection
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| congestive heart failure | DOID:6000 | J:243730 | ||
| dilated cardiomyopathy | DOID:12930 |
OMIM:PS115200 |
J:243730 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• all mice die between 1 and 16 weeks after tamoxifen treatment
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• after tamoxifen treatment
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• both ventricles are severely dilated after tamoxifen treatment
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• both ventricles are severely dilated after tamoxifen treatment
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• decreased heart function one month after tamoxifen treatment
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• after tamoxifen treatment
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• after tamoxifen treatment
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• after tamoxifen treatment
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| dilated cardiomyopathy 1C | DOID:0110423 |
OMIM:601493 |
J:144739 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Enlarged hearts with thinned ventricular walls and enlarged cardiac chambers in Mtortm1.1Gcon/Mtortm1.1Gcon A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice
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• mice start dying at 4 weeks after tamoxifen (TMX) administration; the median survival age is 6 weeks and no mice survive for >8 weeks
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• at 4 weeks after TMX treatment, mice exhibit significantly enlarged hearts relative to controls
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• at 2 weeks after TMX treatment, LV myocardium exhibits sarcomeric disarray and swollen mitochondria, unlike in control hearts
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• at 2 weeks after TMX treatment, cross-sectional area of cardiomyocytes is reduced relative to that in control mice
• adult cardiomyocytes isolated from TMX-treated mice are significantly thinner and shorter than those of control mice
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• atrial chambers are enlarged at 4 weeks after TMX treatment
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• interventricular septum is thinner than normal at 4 weeks after TMX treatment
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• at 4 weeks after TMX treatment, mice exhibit significantly enlarged hearts relative to controls
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• left ventricle (LV) wall is thinner than normal at 4 weeks after TMX treatment
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• ventricular chambers are enlarged at 4 weeks after TMX treatment
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• at 4 weeks after TMX treatment, mice show increased interstitial fibrosis in the LV and interventricular septum relative to controls
• the cardiac fibrotic index is already increased at 1 week after TMX treatment and becomes significantly increased thereafter
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• TMX-treated mice develop lethal dilated cardiomyopathy
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• TMX-treated mice show markedly lower basal inotropy and lusitropy and only very weak reactivity to stimulation with increasing units of dobutamine
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• at 4 weeks after TMX treatment, LV fractional shortening percentage (LVFS %) is significantly reduced relative to that in controls
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• in culture, adult ventricular myocytes isolated from TMX-treated mice show significantly reduced protein synthesis relative to controls, as assessed by a [3H]leucine uptake assay
• TMX-treated mice show a progressive (2- to 8-fold) increase in the expression of cardiac fetal genes (Nppa, Myh7, Acta1) relative to controls at 2 weeks and 4 weeks post-TMX
• TMX-treated mice show a progressive reduction in cytochrome c oxidase subunit IV (CoxIV) expression, indicating a loss in the oxidative capacity of myocardial mitochondria
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• at 2 weeks after transverse aortic constriction (TAC), i.e. 3 weeks post-TMX treatment, mice show an impaired hypertrophic response and accelerated heart failure progression, as determined by a significantly reduced increase in LV wall thickness, a more dilated LV chamber, a significantly reduced ratio of LV weight- and heart weight-to-tibial length, accelerated contractile dysfunction, reduced induction of cardiac fetal genes, and significantly reduced survival relative to control TAC mice, with a 40% death rate already noted after 1 week of TAC
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• at 4 weeks after TMX treatment, mice exhibit heart failure, as assessed by echocardiography and the dobutamine stress test
• however, cardiac function is maintained up to 2-3 weeks after TMX treatment
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• at 4 weeks after TMX treatment, mice show increased interstitial fibrosis in the LV and interventricular septum relative to controls
• the cardiac fibrotic index is already increased at 1 week after TMX treatment and becomes significantly increased thereafter
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• at 2 weeks after TMX treatment, LV myocardium exhibits swollen mitochondria, unlike in control hearts
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• at 1 week after TMX treatment, cardiac expression of several autophagy-related proteins is increased and autophagic bodies are observed in the myocardium, unlike in control hearts
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• TMX-treated mice show a progressive and severe loss of cardiomyocytes due to apoptosis, as shown by TUNEL staining
• at 4 weeks after TMX treatment, cleaved Parp expression is significantly increased in the heart relative to that in control mice
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• TMX-treated mice show a progressive reduction in cytochrome c oxidase subunit IV (CoxIV) expression, indicating reduced oxidative capacity of myocardial mitochondria
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• in culture, adult ventricular myocytes isolated from TMX-treated mice show significantly reduced protein synthesis relative to controls, as assessed by a [3H]leucine uptake assay
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• at 2 weeks after transverse aortic constriction (TAC), i.e. 3 weeks post-TMX treatment, mice show an impaired hypertrophic response and accelerated heart failure progression, as determined by a significantly reduced increase in LV wall thickness, a more dilated LV chamber, a significantly reduced ratio of LV weight- and heart weight-to-tibial length, accelerated contractile dysfunction, reduced induction of cardiac fetal genes, and significantly reduced survival relative to control TAC mice, with a 40% death rate already noted after 1 week of TAC
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• at 1 week after TMX treatment, cardiac expression of several autophagy-related proteins is increased and autophagic bodies are observed in the myocardium, unlike in control hearts
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• in culture, adult ventricular myocytes isolated from TMX-treated mice show significantly reduced protein synthesis relative to controls, as assessed by a [3H]leucine uptake assay
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• TMX-treated mice exhibit pleural effusions
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• at 2 weeks after TMX treatment, LV myocardium exhibits sarcomeric disarray and swollen mitochondria, unlike in control hearts
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• at 2 weeks after TMX treatment, cross-sectional area of cardiomyocytes is reduced relative to that in control mice
• adult cardiomyocytes isolated from TMX-treated mice are significantly thinner and shorter than those of control mice
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• TMX-treated mice develop lethal dilated cardiomyopathy
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• TMX-treated mice show markedly lower basal inotropy and lusitropy and only very weak reactivity to stimulation with increasing units of dobutamine
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• at 4 weeks after TMX treatment, LV fractional shortening percentage (LVFS %) is significantly reduced relative to that in controls
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• TMX-treated mice show a progressive and severe loss of cardiomyocytes due to apoptosis, as shown by TUNEL staining
• at 4 weeks after TMX treatment, cleaved Parp expression is significantly increased in the heart relative to that in control mice
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• at 2 weeks after TMX treatment, LV myocardium exhibits sarcomeric disarray, unlike in control hearts
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• TMX-treated mice exhibit pleural effusions
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• mice die within 3 weeks of tamoxifen treatment
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• vetricular cardiomyocytes from tamoxifen-treated mice exhibit reduced current-voltage relation of current compared with cells from control mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• tamoxifen-treated mice exhibit sudden cardiac death
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• in tamoxifen-treated mice
• however, compensatory mechanisms transiently ameliorate detrimental effects
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• severe in tamoxifen-treated mice
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• in tamoxifen-treated mice
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• in tamoxifen-treated mice
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• repetitive episodes of tachycardic arrhythmia in tamoxifen-treated mice
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• secondary in tamoxifen-treated mice
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• distinct T wave in tamoxifen-treated mice
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• in tamoxifen-treated mice
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• in tamoxifen-treated mice
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• in tamoxifen-treated mice
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• in tamoxifen-treated mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• tamoxifen-treated mice show increased mortality
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• tamoxifen-treated mice develop greatly enlarged heart 16 days after induction
|
|
|
• tamoxifen-treated mice exhibit impaired cardiac fuel utilization
|
|
|
• tamoxifen-treated mice develop dilated cardiomyopathy, showing increased left ventricular interior dimension, reduced fractional shortening, and decreased relative wall thickness
|
|
|
• 16 days after induction with tamoxifen, mice exhibit contractile dysfunction analogous to end-stage dilated cardiomyopathy
|
|
|
• mitochondria exhibit increased distance between cristae in the heart 9 days after induction with tamoxifen
|
|
|
• mitochondria exhibit a round in the heart 9 days after induction with tamoxifen
|
|
|
• tamoxifen-treated hearts exhibit reduced glucose oxidation rates ex vivo
|
|
|
• reduction of enzyme activities of complexes I, II, III, and IV is isolated mitochondria of ventricles from tamoxifen-treated mice
• mitochondrial protein function is compromised in hearts of tamoxifen-treated mice, with a reduction of mitochondrial aconitase activity
• however, the number and density of mitochondria are normal in hearts
|
|
|
• mitochondrial respiration rate is lower in heart 4 days after induction with tamoxifen when cardiac dysfunction is not yet observed
|
|
|
• higher levels of oxidized proteins are seen in heart mitochondria of day 9 of induction with tamoxifen
• decrease of mitochondrial oxygen consumption rate and lower mitochondrial ATP content in hearts of tamoxifen-treated mice, suggesting a reduction in oxidative phosphorylation capacity and ATP production in mitochondria
|
|
|
• tamoxifen-treated hearts exhibit a lower oleate oxidation rate ex vivo
|
|
|
• tamoxifen-treated hearts exhibit a lower oleate oxidation rate ex vivo
|
|
|
• tamoxifen-treated hearts show decreased oxygen consumption rate
|
|
|
• tamoxifen-treated mice develop dilated cardiomyopathy, showing increased left ventricular interior dimension, reduced fractional shortening, and decreased relative wall thickness
|
|
|
• 16 days after induction with tamoxifen, mice exhibit contractile dysfunction analogous to end-stage dilated cardiomyopathy
|
|
|
• tamoxifen-treated mice develop greatly enlarged heart 16 days after induction
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| dilated cardiomyopathy | DOID:12930 |
OMIM:PS115200 |
J:227012 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• average survival time of 11.9 +/- 3 days following tamoxifen treatment for 5 days
|
|
• increase in ventricular end diastolic volume after tamoxifen treatment
|
|
• profound decrease in myocardial contractility, as assessed by fractional shortening, after tamoxifen treatment
|
|
• profound decrease in myocardial contractility, as assessed by fractional shortening, after tamoxifen treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice die starting around 11 days post tamoxifen injection, with most dying by day 14
|
|
• 12 days post tamoxifen treatment, mice exhibit a reduced basal heart rate
• tamoxifen treated mice, however, do not exhibit stress-induced (by caffeine or epinephrine) ventricular tachyarrhythmias at young or older ages
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• after tamoxifen (TMX) treatment, mice exhibit significantly enhanced survival relative to Mtortm1.1Gcon/Mtortm1.1Gcon A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice
|
|
N |
• at 4 weeks after TMX treatment, mice exhibit normal echocardiographic parameters, cardiomyocyte size, and cardiac function (as assessed by the LV fractional shortening %)
|
|
|
• at 4 weeks after TMX treatment, mice show significantly reduced fibrosis relative to Mtortm1.1Gcon/Mtortm1.1Gcon A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice
|
|
|
• at 4 weeks after TMX treatment, mice show significantly reduced fibrosis relative to Mtortm1.1Gcon/Mtortm1.1Gcon A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice
|
|
|
• after TMX treatment, mice show a similar expression of autophagy genes relative to Mtortm1.1Gcon/Mtortm1.1Gcon A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice, suggesting that autophagy is not involved in the amelioration of the heart failure phenotype
|
|
|
• at 4 weeks after TMX treatment, mice show a significant decrease of cleaved Parp protein and TUNEL+ cells in the myocardium relative to Mtortm1.1Gcon/Mtortm1.1Gcon A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice
|
|
|
• at 4 weeks after TMX treatment, mice show increased cytochrome c oxidase subunit IV (CoxIV) expression in heart lysates relative to Mtortm1.1Gcon/Mtortm1.1Gcon A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice, suggesting that mitochondrial function is improved
|
|
|
• at 4 weeks after TMX treatment, mice show a significant decrease of cleaved Parp protein and TUNEL+ cells in the myocardium relative to Mtortm1.1Gcon/Mtortm1.1Gcon A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice
|
|
|
• after TMX treatment, mice show a similar expression of autophagy genes relative to Mtortm1.1Gcon/Mtortm1.1Gcon A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice, suggesting that autophagy is not involved in the amelioration of the heart failure phenotype
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hearts of mutants treated with tamoxifen for 3 weeks to induce cre-expression develop significantly better function recovery in response to 30 min ischemia followed by 120 min reperfusion than controls, showing significantly improved end-diastolic pressure, left ventricle developed pressure (LVDP) and LVDP recoveries, and improved systolic and diastolic contractility of hearts
• at 60 min post reperfusion, recovery of left ventricular diastolic pressure reaches 77.9% of pre-ischemia in hearts versus 44% in controls
• hearts have significantly fewer apoptosis positive cardiomyocytes after ischemia/reperfusion (I/R) injury than controls
|
|
• mutants treated with tamoxifen to induce cre-expression exhibit a significant reduction in infarct size after ischemia
|
|
• hearts of mutants treated with tamoxifen for 3 weeks to induce cre-expression develop significantly better function recovery in response to 30 min ischemia followed by 120 min reperfusion than controls, showing significantly improved end-diastolic pressure, left ventricle developed pressure (LVDP) and LVDP recoveries, and improved systolic and diastolic contractility of hearts
• at 60 min post reperfusion, recovery of left ventricular diastolic pressure reaches 77.9% of pre-ischemia in hearts versus 44% in controls
• hearts have significantly fewer apoptosis positive cardiomyocytes after ischemia/reperfusion (I/R) injury than controls
|
|
• mutants treated with tamoxifen to induce cre-expression exhibit a significant reduction in infarct size after ischemia
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• robust increase in glucose uptake in 4-hydroxytamoxifen treated mice compared to controls
|
|
• mice treated with 4-hydroxytamoxifen to induce recombination display a decrease in pressure overload induced progressive hypertrophy during the early phase compared to controls
|
|
• robust increase in glucose uptake in 4-hydroxytamoxifen treated mice compared to controls
|
|
• mice treated with 4-hydroxytamoxifen to induce recombination display a decrease in pressure overload induced progressive hypertrophy during the early phase compared to controls
|
|
• robust increase in glucose uptake in 4-hydroxytamoxifen treated mice compared to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• hearts of tamoxifen-treated mice exhibit normal cardiac adaptation to long-term stress induced by transverse aortic constriction
|
|
• tamoxifen-treated mice exhibit inhibited acute cardiac mitochondrial calcium uptake compared with control cells
• at 18 weeks, cardiac myocytes from tamoxifen-treated mice challenged with calcium exhibit a severely blunted compared with control cells
• cardiac myocytes from tamoxifen-treated mice exhibit lower sodium-induced calcium efflux rates compared with control cells
• cardiac mitochondria from mice treated with tamoxifen and dobutamine fail to exhibit an increase in calcium unlike control mitochondria
• however, mice exhibit normal baseline mitochondrial calcium levels, response to Ru360, and elevated calcium levels in the mitochondrial following sustained dobutamine treatment
|
|
• tamoxifen-treated mice subjected to dobutamine (the beta-adrenergic receptor agonist) exhibit lesser short-term increase in the maximal rate of cardiac pressure compared with control mice
• however, sustained administration of dobutamine at 32 ng/g/min induced similar ventricular pressure
|
|
• cardiomyocytes from tamoxifen treated mice fail to exhibit an increase in mitochondrial oxygen consumption and ATP utilization compared with control mice
• however, baseline mitochondrial oxygen consumption and ATP utilization are normal
|
|
• in tamoxifen treated mice
|
|
• under the short warm-up/high-intensity sprinting regimen, tamoxifen-treated mice exhibit reduced running capacity compared with control mice
• however, the difference is lost with a longer warm-up period
|
|
• in tamoxifen treated mice
|
|
• under the short warm-up/high-intensity sprinting regimen, tamoxifen-treated mice exhibit reduced running capacity compared with control mice
• however, the difference is lost with a longer warm-up period
|
|
• in cardiomyocytes from tamoxifen treated mice in response to ionomycin
|
|
• tamoxifen-treated mice exhibit inhibited acute cardiac mitochondrial calcium uptake compared with control cells
• at 18 weeks, cardiac myocytes from tamoxifen-treated mice challenged with calcium exhibit a severely blunted compared with control cells
• cardiac myocytes from tamoxifen-treated mice exhibit lower sodium-induced calcium efflux rates compared with control cells
• cardiac mitochondria from mice treated with tamoxifen and dobutamine fail to exhibit an increase in calcium unlike control mitochondria
• however, mice exhibit normal baseline mitochondrial calcium levels, response to Ru360, and elevated calcium levels in the mitochondrial following sustained dobutamine treatment
|
|
• tamoxifen-treated mice subjected to dobutamine (the beta-adrenergic receptor agonist) exhibit lesser short-term increase in the maximal rate of cardiac pressure compared with control mice
• however, sustained administration of dobutamine at 32 ng/g/min induced similar ventricular pressure
|
|
• in cardiomyocytes from tamoxifen treated mice in response to ionomycin
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in tamoxifen-treated mice
|
|
• mildly in tamoxifen-treated mice
|
|
• posterior wall thickness in tamoxifen-treated mice is slightly decreased compared to in wild-type mice
|
|
• in tamoxifen-treated mice
|
|
• myocytes of tamoxifen-treated mice exhibit reduced inward calcium ion current density compared with wild-type cells
|
|
• in tamoxifen-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• in tamoxifen-treated mice exhibit normal myocyte reduced inward calcium ion current density
|
|
• slightly in tamoxifen-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• some mice die by 3 weeks of age
• however, some mice are viable
|
|
• cardiomyocyte mitochondria exhibit almost no calcium uptake in response to extramitochondrial calcium ion pulses unlike control cells
• cardiomyocytes mitochondria exhibit defective inward mitochondrial calcium ion uniporter-dependent inward current compared with control cells
• however, mitochondrial membrane potential is normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• near complete rescue in tamoxifen-treated mice
|
|
• near complete rescue in tamoxifen-treated mice
|
|
• near complete rescue in tamoxifen-treated mice
|
|
• near complete rescue in tamoxifen-treated mice
|
|
• disorganization is nearly completely rescued in tamoxifen-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• most mice died within two weeks of tamoxifen treatment
|
|
• increased cross-sectional area post tamoxifen-treatment
|
|
• post tamoxifen-treatment
|
|
• post tamoxifen-treatment
|
|
• 3 days post tamoxifen-treatment
|
|
• post tamoxifen-treatment
|
|
• decreased left ventricular function 3 days post tamoxifen-treatment as measured by fractional shortening and left ventricular end-diastolic dimension
|
|
• post tamoxifen-treatment
|
|
• post tamoxifen-treatment only immediately before sinus arrest
|
|
• post tamoxifen-treatment
|
|
• post tamoxifen-treatment
|
|
• post tamoxifen-treatment
|
|
• post tamoxifen-treatment
|
|
• post tamoxifen-treatment
|
|
• increased cross-sectional area post tamoxifen-treatment
|
|
• decreased left ventricular function 3 days post tamoxifen-treatment as measured by fractional shortening and left ventricular end-diastolic dimension
|
|
• disorganized post tamoxifen-treatment
|
|
• with disrupted calcium regulation in cardiomyocytes post tamoxifen-treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants die about 2 months after tamoxifen treatment
|
|
• after tamoxifen treatment enlarged hyperchromatic myocyte nuclei are seen
• after tamoxifen treatment intercalated disc structures and intercellular space are absent
• after tamoxifen treatment sarcomeres appear distorted and compressed with wider, less dense Z-lines
|
|
• after tamoxifen treatment intercalated disc structures are absent
|
|
• modest dilation of the atria after tamoxifen treatment
|
|
• after tamoxifen treatment hearts appear elongated and flacid
|
|
• modest dilation of the ventricles after tamoxifen treatment
|
|
• modest dilation of the ventricles after tamoxifen treatment
|
|
• left ventricular end-diastolic and end-systolic volume in the cavity are increased and left ventricular ejection fraction is decreased
|
|
• about 5 weeks after tamoxifen treatment, mutant heart rate is significantly reduced
|
|
• about 6 weeks after tamoxifen treatment, 2 mutants showed abrupt onset of ventricular tachyarrhythmia followed by sudden death
|
|
• about 6 weeks after tamoxifen treatment, 2 mutants showed abrupt onset of ventricular tachyarrhythmia followed by sudden death
|
|
• tachyarrhythmia is initiated by premature ventricular depolarization
|
|
• after tamoxifen treatment enlarged hyperchromatic myocyte nuclei are seen
• after tamoxifen treatment intercalated disc structures and intercellular space are absent
• after tamoxifen treatment sarcomeres appear distorted and compressed with wider, less dense Z-lines
|
|
• after tamoxifen treatment intercalated disc structures are absent
|
|
• left ventricular end-diastolic and end-systolic volume in the cavity are increased and left ventricular ejection fraction is decreased
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 80% increase in cardiomyocyte cross-section 10 weeks after tamoxifen treatment
|
|
• heart weight to body weight ratio is increased by 300% 10 weeks after tamoxifen treatment
|
|
• severe cardiac hypertrophy and myopathy, but no fibrosis 10 weeks after tamoxifen treatment
|
|
• reduced fractional shortening with greater left ventricular chamber in diastole 10 weeks after tamoxifen treatment
|
|
• severe cardiac hypertrophy and myopathy, but no fibrosis 10 weeks after tamoxifen treatment
|
|
• rate of mitochondrial ATP synthesis is decreased by 45% following tamoxifen administration, however, cardiac ventricular performance is not affected and 10 weeks after treatment ATP levels are unchanged
• mitochondrial inorganic phosphate (Pi) uptake is decreased in cardiac mitochondria two weeks after tamoxifen administration
|
|
• mitochondrial hyperproliferation occurs 10 weeks after tamoxifen treatment
|
|
• sarcoplasmic reticulum Ca2+ load is increased following tamoxifen administration, however, overall Ca2+ reuptake time is not changed
|
|
• 80% increase in cardiomyocyte cross-section 10 weeks after tamoxifen treatment
|
|
• reduced fractional shortening with greater left ventricular chamber in diastole 10 weeks after tamoxifen treatment
|
|
• severe cardiac hypertrophy and myopathy, but no fibrosis 10 weeks after tamoxifen treatment
|
|
• sarcomeric disarray with fragmented and disrupted mitochondria 10 weeks after tamoxifen treatment
|
|
• swelling of the mitochondrial permeability transition pore (MPTP) as a result of Ca2+ overload is reduced as compared to wild-type in cardiac mitochondria following tamoxifen administration
|
|
• heart weight to body weight ratio is increased by 300% 10 weeks after tamoxifen treatment
|
|
• severe cardiac hypertrophy and myopathy, but no fibrosis 10 weeks after tamoxifen treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following transverse aortic constriction, mice exhibit diminished cardiac hypertrophy compared with control mice
|
|
• following transverse aortic constriction, mice exhibit diminished cardiac hypertrophy compared with control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• treatment of mice with oral dose of 160 mg/kg BW per day raloxifene for 21 days resulted in similar recombinase activity as the tamoxifen regimen, but does not cause any cardiac dysfunction; lower (20 mg/kg BW) oral tamoxifen treatment for 21 days does not cause dysfunction
|
|
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
|
|
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing significantly
|
|
• by 6 days following IP tamoxifen treatment (80 mg/kg BW for 5 days), 60% mortality of treated mice is observed
|
|
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
|
|
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing significantly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• increase in cardiac death compared to controls beginning about 3 months after tamoxifen treatment
|
| N |
• unlike in human patients with Arrhythmogenic Right Ventricular Dysplasia replacement of myocytes with adipocytes is not seen in tamoxifen treated mice and tamoxifen treated mice are not more susceptible to induced arrhythmias
|
|
• decrease in the number and length of desmosomes in tamoxifen treated mice
• adherens-type junctions with less submembranous electron-dense material are prominently seen in tamoxifen treated mice
|
|
• mislocalization of desmosomal proteins to the intercalated disc in tamoxifen treated mice
|
|
• increase in cardiomyocyte cross sectional area with age in tamoxifen treated mice
|
|
• increase in the heart to body weight ratio with age in tamoxifen treated mice
|
|
• by about 5 months after tamoxifen treatment
|
|
• mild left ventricle hypertrophy in tamoxifen treated mice
|
|
• modest left ventricle dilation in tamoxifen treated mice
|
|
• progressive thinning of the right ventricular free wall is seen after tamoxifen treatment
|
|
• by about 5 months after tamoxifen treatment
|
|
• focal areas of myocyte loss and replacement with fibrous tissue are seen after tamoxifen treatment
|
|
• increased apoptosis is seen at 5 months after tamoxifen treatment
• apoptotic cells are associated with fibrotic areas
• heart failure is seen in some tamoxifen treated mice
|
|
• reduction of left ventricular fractional shortening and ejection fraction in tamoxifen treated mice
|
|
• infiltration of activated macrophages/monocytes in areas adjacent to apoptotic myocytes in tamoxifen treated mice
• neutrophil infiltrations are also seen in tamoxifen treated mice
|
|
• decrease in the number and length of desmosomes in tamoxifen treated mice
• adherens-type junctions with less submembranous electron-dense material are prominently seen in tamoxifen treated mice
|
|
• mislocalization of desmosomal proteins to the intercalated disc in tamoxifen treated mice
|
|
• increase in cardiomyocyte cross sectional area with age in tamoxifen treated mice
|
|
• mild left ventricle hypertrophy in tamoxifen treated mice
|
|
• reduction of left ventricular fractional shortening and ejection fraction in tamoxifen treated mice
|
|
• cardiomyocyte sarcomeres appear distorted and compressed in tamoxifen treated mice
• decreased cardiomyocyte sarcomere length in tamoxifen treated mice
|
|
• cardiomyocyte sarcomeres have wider, less dense Z lines in tamoxifen treated mice
|
|
• seen at 9 - 12 months after tamoxifen treatment, associated with heart failure
|
|
• increase in the IL6 and IL1B levels in heart lysates from tamoxifen treated mice
• increase in cytokine expression is associated with the severity of myocyte loss
|
|
• infiltration of activated macrophages/monocytes in areas adjacent to apoptotic myocytes in tamoxifen treated mice
• neutrophil infiltrations are also seen in tamoxifen treated mice
|
|
• increase in the IL6 and IL1B levels in heart lysates from tamoxifen treated mice
• increase in cytokine expression is associated with the severity of myocyte loss
|
|
• seen at 9 - 12 months after tamoxifen treatment, associated with heart failure
|
|
• mild left ventricle hypertrophy in tamoxifen treated mice
|
|
• increase in the heart to body weight ratio with age in tamoxifen treated mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| arrhythmogenic right ventricular dysplasia 12 | DOID:0110083 |
OMIM:611528 |
J:170618 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• when treated with tamoxifen at 2 months of age, mice begin to die at 56 days after the first tamoxifen injection, and none survive past 104 days
|
|
• F-actin accumulations are observed within myofibrils at 1 month after the first tamoxifen injection
|
|
• cardiomyocyte size is increased at 1 month after the first tamoxifen injection
|
|
|
• in male mice, the heart weight/body weight ratio begins to increase at 1 month after the first tamoxifen injection
• however, no significant changes are observed in tamoxifen-treated female mice
|
|
• tamoxifen-treated mice exhibit a milder heart hypertrophy relative to that observed in mice that are homozygous for Wdr1tm1.1Zzy and hemizygous for Tg(Myhc-cre)1Xya
|
|
• F-actin accumulations are observed within myofibrils at 1 month after the first tamoxifen injection
|
|
• cardiomyocyte size is increased at 1 month after the first tamoxifen injection
|
|
|
• in male mice, the heart weight/body weight ratio begins to increase at 1 month after the first tamoxifen injection
• however, no significant changes are observed in tamoxifen-treated female mice
|
|
• tamoxifen-treated mice exhibit a milder heart hypertrophy relative to that observed in mice that are homozygous for Wdr1tm1.1Zzy and hemizygous for Tg(Myhc-cre)1Xya
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants die about 2 months after tamoxifen treatment
|
|
• after tamoxifen treatment enlarged hyperchromatic myocyte nuclei are seen
• after tamoxifen treatment intercalated disc structures and intercellular space are absent
• after tamoxifen treatment sarcomeres appear distorted and compressed with wider, less dense Z-lines
|
|
• after tamoxifen treatment intercalated disc structures are absent
|
|
• modest dilation of the atria after tamoxifen treatment
|
|
• after tamoxifen treatment hearts appear elongated and flacid
|
|
• modest dilation of the ventricles after tamoxifen treatment
|
|
• modest dilation of the ventricles after tamoxifen treatment
|
|
• eft ventricular end-diastolic and end-systolic volume in the cavity are increased and left ventricular ejection fraction is decreased
|
|
• about 5 weeks after tamoxifen treatment, mutant heart rate is significantly reduced
|
|
• about 6 weeks after tamoxifen treatment, 2 mutants showed abrupt onset of ventricular tachyarrhythmia followed by sudden death
|
|
• about 6 weeks after tamoxifen treatment, 2 mutants showed abrupt onset of ventricular tachyarrhythmia followed by sudden death
|
|
• tachyarrhythmia is initiated by premature ventricular depolarization
|
|
• after tamoxifen treatment enlarged hyperchromatic myocyte nuclei are seen
• after tamoxifen treatment intercalated disc structures and intercellular space are absent
• after tamoxifen treatment sarcomeres appear distorted and compressed with wider, less dense Z-lines
|
|
• after tamoxifen treatment intercalated disc structures are absent
|
|
• eft ventricular end-diastolic and end-systolic volume in the cavity are increased and left ventricular ejection fraction is decreased
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• by 6 days following IP tamoxifen treatment (80 mg/kg BW for 5 days), 60% mortality of treated mice is observed
|
| N |
• treatment of mice with oral dose of 160 mg/kg BW per day raloxifene for 21 days resulted in similar recombinase activity as the tamoxifen regimen, but does not cause any cardiac dysfunction; lower (20 mg/kg BW) oral tamoxifen treatment for 21 days does not cause dysfunction
|
|
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
|
|
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing significantly
|
|
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
|
|
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing significantly
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• develop severe bradycardia when injected daily with tamoxifen which leads eventually to death
• heart rate reduced by 32% after 2 days of treatment and by 47% after 6 days
• isolated cells from the sino-atrial node of mice treated with tamoxifen beat spontaneously but more slowly than control cells and become progressively slower as treatment is continued to 5 days
• mice injected with isoproterenol experience heart beat acceleration similar to that occurring in control mice
|
|
• when injected daily with tamoxifen, atrioventricular block becomes a 2nd degree block
• conduction ratio progresses from 2:1 to 4:1 or more
|
|
• when mice are injected daily with tamoxifen, a prolonged PQ interval is observed
|
|
• f-channel current densities from atrioventricular cells isolated from mice after 2 and 5 days of treatment with tamoxifen are lower than for control cells
• there is a time dependent decrease in f-channel conductance
|
|
• no mice survive beyond 8.5 days of treatment with tamoxifen
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• cardiomyocyte fiber cross-sectional area is increased following tamoxifen treatment
• however, cardiomyocyte fibers are otherwise normal
|
|
• increase in the heart to body weight ratio following tamoxifen treatment
|
|
• following tamoxifen treatment
|
|
• following tamoxifen treatment
|
|
• calcium cycling is impaired following tamoxifen treatment
• decrease in the autophagy levels following tamoxifen treatment
|
|
• increase in the lung to body weight ratio following tamoxifen treatment
|
|
• cardiomyocyte fiber cross-sectional area is increased following tamoxifen treatment
• however, cardiomyocyte fibers are otherwise normal
|
|
• following tamoxifen treatment
|
|
• increase in the heart to body weight ratio following tamoxifen treatment
|
|
• increase in the lung to body weight ratio following tamoxifen treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• hypertrophy of cardiomyocytes occurs after 6 weeks of aortic banding to mice that have had cre expression induced
|
|
• left ventricular end systolic volume is increased after cre induction from 0.017 cm3/g to 0.021 cm3/g
|
|
• after cre induction, the left ventricular ejection fraction is depressed from 0.65 cm3/g to 0.60 cm3/g
|
|
• heart rate is depressed after cre induction from 443 bpm to 441 bpm
|
|
• male mice with cre induction and intracardiac electrical stimulation have more ventricular tachycardia episodes than controls (17 vs. 3)
• duration of these episodes are also about 3-fold longer than controls
|
|
• mice in which cre expression is induced have more weight loss than controls in response to exercise
|
|
• mice with cre expression have a reduced exercise capacity
|
|
• hypertrophy of cardiomyocytes occurs after 6 weeks of aortic banding to mice that have had cre expression induced
|
|
• after cre induction, the left ventricular ejection fraction is depressed from 0.65 cm3/g to 0.60 cm3/g
|
|
• mice with cre expression have a reduced exercise capacity
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 4 month old mice treated with tamoxifen become lethargic within 3-4 days of tamoxifen exposure and die within 7 days
|
|
• derangements in cardiomyocyte structure and myofibrillar organization are seen throughout the hearts of tamoxifen-treated adult mice
• myofibrillar striations are absent in tamoxifen-treated hearts
• cardiomyocytes of tamoxifen-treated adult mice exhibit indistinct desmosomes and adherens junctions
|
|
• structure of the intercalated disc is disrupted in the hearts of tamoxifen-treated adult mice
|
|
• loss of cardiomyocytes in tamoxifen-treated adults
|
|
• cardiomyocyte disarray with myocyte loss in hearts of tamoxifen-treated adult mice
• sparse, randomly oriented myofibers are seen throughout the sarcoplasm of hearts of tamoxifen-treated adult mice
|
|
• hearts of tamoxifen-treated adult mice are enlarged
|
|
• hearts of tamoxifen-treated adult mice show large pericardial effusions
|
|
• fibrosis in hearts of tamoxifen-treated adult mice
|
|
• 6 days after tamoxifen treatment, adult mice exhibit severe dilated cardiomyopathy involving all 4 chambers
|
|
• mean ejection fraction is decreased in tamoxifen-treated adult mice
|
|
• hearts of tamoxifen-treated adult mice are enlarged
|
|
• widespread cardiomyocyte apoptosis in tamoxifen-treated adult mice
|
|
• hearts of tamoxifen-treated adult mice show large pericardial effusions
|
|
• derangements in cardiomyocyte structure and myofibrillar organization are seen throughout the hearts of tamoxifen-treated adult mice
• myofibrillar striations are absent in tamoxifen-treated hearts
• cardiomyocytes of tamoxifen-treated adult mice exhibit indistinct desmosomes and adherens junctions
|
|
• structure of the intercalated disc is disrupted in the hearts of tamoxifen-treated adult mice
|
|
• loss of cardiomyocytes in tamoxifen-treated adults
|
|
• cardiomyocyte disarray with myocyte loss in hearts of tamoxifen-treated adult mice
• sparse, randomly oriented myofibers are seen throughout the sarcoplasm of hearts of tamoxifen-treated adult mice
|
|
• 6 days after tamoxifen treatment, adult mice exhibit severe dilated cardiomyopathy involving all 4 chambers
|
|
• mean ejection fraction is decreased in tamoxifen-treated adult mice
|
|
• widespread cardiomyocyte apoptosis in tamoxifen-treated adult mice
|
|
• loss of sarcomeres in the hearts of tamoxifen-treated adult mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| dilated cardiomyopathy | DOID:12930 |
OMIM:PS115200 |
J:154666 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• progressive 8 months after tamoxifen treatment
|
|
• progressive 8 months after tamoxifen treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Inhibition of dilated cardiomyopathy in Dmdtm1.1Know/Dmdtm1.1Know Tg(Myh6-2A)#Know/0 A1cfTg(Myh6-cre/Esr1*)1Jmk/0 mice
|
• less severe fibrosis in tamoxifen-treated mice
|
|
• improved cardiac function in tamoxifen-treated mice
|
|
• improved cardiac function in tamoxifen-treated mice
|
|
• less severe cardiomyopathy in tamoxifen-treated mice
|
|
• tamoxifen-treated mice exhibit less severe cardiomyopathy, cardiac fibrosis and improved cardiac function compared with control mice
|
|
• improved cardiac function in tamoxifen-treated mice
|
|
• less severe cardiomyopathy in tamoxifen-treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• cardiac cells from tamoxifen-treated mice show severe cytoskeletal changes such as myofibrillar collapse with a haphazard arrangement, a decrease in myofibril number, and an increase in swollen mitochondria
• irregularity in the spacing between cells in the intercalated discs and irregularity of the sarcolemmal membrane in the hearts of tamoxifen-treated mice
|
|
|
• myocardial fibers of tamoxifen-treated mice show abnormalities of intercalated discs
|
|
|
• biatrial enlargement in tamoxifen-treated mice
|
|
|
• severe ventricular enlargement in tamoxifen-treated mice
|
|
|
• small amount of interstitial fibrosis in tamoxifen-treated mice
|
|
|
• heart weight-to-body weight ratio is increased 22 days after tamoxifen administration
|
|
|
• decrease in the fractional shortening of the left ventricle of tamoxifen-treated mice
|
|
|
• increase in left ventricular end-diastolic dimension and end-systolic dimension in tamoxifen-treated mice
|
|
|
• tamoxifen-treated mice show only a small increase in inflammation
|
|
|
• in tamoxifen-treated mice
|
|
|
• tamoxifen-treated mice show only a small increase in inflammation
|
|
|
• cardiac cells from tamoxifen-treated mice show severe cytoskeletal changes such as myofibrillar collapse with a haphazard arrangement, a decrease in myofibril number, and an increase in swollen mitochondria
• irregularity in the spacing between cells in the intercalated discs and irregularity of the sarcolemmal membrane in the hearts of tamoxifen-treated mice
|
|
|
• myocardial fibers of tamoxifen-treated mice show abnormalities of intercalated discs
|
|
|
• heart weight-to-body weight ratio is increased 22 days after tamoxifen administration
|
|
|
• decrease in the fractional shortening of the left ventricle of tamoxifen-treated mice
|
|
|
• the sarcolemmal membrane is disrupted in myocardial fibers of tamoxifen-treated mice
|
|
|
• myocardial fibers from tamoxifen-treated mice show shortened sarcomeres
|
|
|
• myocardial fibers from tamoxifen-treated mice show fuzzy Z-lines
|
|
|
• in tamoxifen-treated mice
|
|
|
• small amount of interstitial fibrosis in tamoxifen-treated mice
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| dilated cardiomyopathy | DOID:12930 |
OMIM:PS115200 |
J:128060 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• all mice die within 14 weeks post tamoxifen injection
|
|
|
• mice show enlarged hearts 11 weeks post tamoxifen injection
|
|
|
• ratio of ventricular weight to body weight is increased at 11 weeks post tamoxifen injection
|
|
|
• ventricular wall thinning is seen at 11 weeks post tamoxifen injection
|
|
|
• ventricular chamber dilation is seen at 11 weeks post tamoxifen injection
|
|
|
• hearts show severe cardiac fibrosis at 11 weeks post tamoxifen injection
|
|
|
• increase in number of apoptotic cells is seen in hearts at 11 weeks post tamoxifen injection
|
|
|
• mice develop dilated cardiomyopathy after tamoxifen injection
|
|
|
• left ventricle fractional shortening and ejection fraction are slightly decreased at 9 weeks and further decreased at 11 and 13 weeks after tamoxifen injection
|
|
|
• left ventricle systolic function represented by fractional shortening and ejection fraction is slightly decreased at 9 weeks post tamoxifen injection and further increased at 11 and 13 weeks after tamoxifen injection
• enlarged left ventricle chamber and ventricular wall thinning are seen at 11 and 13 weeks after tamoxifen injection
• left ventricle systolic function further deteriorates at 11 and 13 weeks after tamoxifen injection
• however, ventricular wall thickness and internal dimension of the heart are not altered at 9 weeks post tamoxifen injection
|
|
|
• mice develop dilated cardiomyopathy and heart failure after tamoxifen injection
|
|
|
• activities of complex I and complex III in mitochondria are impaired at 9 weeks post tamoxifen injection
• activities of all four complexes in mitochondria are impaired at 11 weeks post tamoxifen injection
• cardiomyocytes show reduced mitochondrial potential and increased mitochondrial ROS levels at 9 weeks post tamoxifen injection
|
|
|
• cardiomyocytes show increased mitochondrial ROS levels at 9 weeks post tamoxifen injection
|
|
|
• mice develop dilated cardiomyopathy after tamoxifen injection
|
|
|
• left ventricle fractional shortening and ejection fraction are slightly decreased at 9 weeks and further decreased at 11 and 13 weeks after tamoxifen injection
|
|
|
• ratio of lung weight to body weight are increased at 11 weeks post tamoxifen injection
|
|
|
• mice show enlarged hearts 11 weeks post tamoxifen injection
|
|
|
• ratio of lung weight to body weight are increased at 11 weeks post tamoxifen injection
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 2.5 fold increase in mononuclear cardiomyocyte frequency
• 3 fold increase in mononuclear diploid cardiomyocytes (MNDCMs)
|
|
• 2.5 fold increase in mononuclear cardiomyocyte frequency
• 3 fold increase in mononuclear diploid cardiomyocytes (MNDCMs)
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• tamoxifen-treated mice exhibit normal left ventricle function and cardiac morphometry and normal left ventricular remodeling after permanent occlusion myoinfarction
|
|
• decreased cell death in tamoxifen-treated mice following ischemic injury
|
|
• following ischemic/reperfusion injury, tamoxifen-treated mice exhibit decreased infarct size and cardiomyocyte cell death compared with wild-type mice
• however, normal left ventricular remodeling after permanent occlusion myoinfarction
|
|
• in tamoxifen-treated mice following ischemic/reperfusion injury
|
|
• following ischemic/reperfusion injury, tamoxifen-treated mice exhibit decreased infarct size and cardiomyocyte cell death compared with wild-type mice
• however, normal left ventricular remodeling after permanent occlusion myoinfarction
|
|
• in tamoxifen-treated mice following ischemic/reperfusion injury
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• tamoxifen treated mice show a similiar response to ischemia/reperfusion injury as controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in tamoxifen treated mice ligation of the left anterior descending coronary artery induces increased thinning of the left ventricular posterior wall and intraventricular septum and increased ventricular dilation
• in tamoxifen treated mice ligation of the left anterior descending coronary artery induces more severe cardiac dysfunction as indicated by significantly reduced fractional shortening and ejection fraction
• however, hearts of tamoxifen treated mice do not show abnormalities prior to ligation of the left anterior descending coronary artery
|
|
• in tamoxifen treated mice at 2 weeks post cardiac infarction left ventricular vessel density is reduced in the infarcted zone and border zone compared to controls
|
|
• increased apoptosis in hearts of tamoxifen treated mice at 24 hours after ligation of the left anterior descending coronary artery
|
|
• in tamoxifen treated mice increased infarct size at 2 weeks after ligation of the left anterior descending coronary artery
|
|
• in tamoxifen treated mice ligation of the left anterior descending coronary artery induces increased thinning of the left ventricular posterior wall and intraventricular septum and increased ventricular dilation
• in tamoxifen treated mice ligation of the left anterior descending coronary artery induces more severe cardiac dysfunction as indicated by significantly reduced fractional shortening and ejection fraction
• however, hearts of tamoxifen treated mice do not show abnormalities prior to ligation of the left anterior descending coronary artery
|
|
• in tamoxifen treated mice at 2 weeks post cardiac infarction left ventricular vessel density is reduced in the infarcted zone and border zone compared to controls
|
|
• increased apoptosis in hearts of tamoxifen treated mice at 24 hours after ligation of the left anterior descending coronary artery
|
|
• in tamoxifen treated mice increased infarct size at 2 weeks after ligation of the left anterior descending coronary artery
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• following 2 weeks of TAC or isoproterenol infusion, left venticle (LV) myocytes from mice administered tamoxifen exhibit an increase in cross section area, but to a much lessor extent than controls subjected to the same regime
|
|
• following a long term (LT) TAC, mice administered tamoxifen die as a result of congenital heart failure, but exhibit greater survival than controls subjected to the same regime (6% vs 29%) and do not exhibit pulmonary edema
|
|
• following cardiac stress by long term transverse aortic constriction (LT-TAC), mice administered tamoxifen exhibit increased left atrial weight (35%) as compared controls undergoing a sham procedure, but less than the increase (50%) in controls subjected to the same regime
|
|
• following a LT-TAC, mice administered tamoxifen die as a result of congenital heart failure, but exhibit greater survival than controls subjected to the same regime (6% vs 29%) and do not exhibit pulmonary edema
|
|
• following 2 weeks of TAC or isoproterenol infusion, mice administered tamoxifen exhibit increased left ventricular (LV) wall thickness, but to a much lessor extent than controls subjected to the same regime
|
|
• following 2 weeks of cardiac stress by transverse aortic constriction (TAC) or isoproterenol infusion, mice administered tamoxifen exhibit increased biventricular weight, but to a much lessor extent than controls subjected to the same regime
• following a 5 week swimming regime, mice administered tamoxifen exhibit an increase in biventricular weight gain, but to a lessor extent than controls subjected to the same regime (13% vs 5%)
|
|
• following a long term LT-TAC, mice administered tamoxifen exhibit increased collagen deposistion, but 78% less collagen deposition as compared controls subjected to the same regime
|
|
• following a 5 week swimming regime, mice administered tamoxifen exhibit lower heart rate than controls subjected to the same regime
|
|
• following a long term (LT) TAC, mice administered tamoxifen die as a result of congenital heart failure, but exhibit greater survival than controls subjected to the same regime (6% vs 29%) and do not exhibit pulmonary edema
|
|
• following a long term LT-TAC, mice administered tamoxifen exhibit increased collagen deposistion, but 78% less collagen deposition as compared controls subjected to the same regime
|
|
• following a long term LT-TAC, mice administered tamoxifen exhibit increased apoptosis, but 75% less myocardial apoptosis as compared controls subjected to the same regime
|
|
• following 2 weeks of TAC or isoproterenol infusion, left venticle (LV) myocytes from mice administered tamoxifen exhibit an increase in cross section area, but to a much lessor extent than controls subjected to the same regime
|
|
• following a long term (LT) TAC, mice administered tamoxifen die as a result of congenital heart failure, but exhibit greater survival than controls subjected to the same regime (6% vs 29%) and do not exhibit pulmonary edema
|
|
• following a long term LT-TAC, mice administered tamoxifen exhibit increased apoptosis, but 75% less myocardial apoptosis as compared controls subjected to the same regime
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding with both interstitial and perivascular spaces but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• after aortic banding, mice exhibit less cardiac hypertrophic response (lower heart and liver weight, smaller heart and smaller cardiomyocytes size) and reduced fibrosis and fractional shortening and ejection fraction compared with wild-type mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• after aortic banding, mice exhibit less cardiac hypertrophic response (lower heart and liver weight, smaller heart and smaller cardiomyocytes size) and reduced fibrosis and fractional shortening and ejection fraction compared with wild-type mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
• 4 weeks after aortic banding but less severe than in control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• cardiac hypertrophy induced by aortic banding is blunted with a smaller increase in heart weight , improved cardiac performance, less pronounced hypertrophic morphological changes, and reduced myocardial fibrosis
|
|
• cardiac hypertrophy induced by aortic banding is blunted with a smaller increase in heart weight , improved cardiac performance, less pronounced hypertrophic morphological changes, and reduced myocardial fibrosis
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• despite the increase in cardiac myosin regulatory light chain phosphorylation after tamoxifen treatment, no difference in heart size is detected
|
|
• in tamoxifen treated mice the ratio of myosin in the SRX state to that in the DRX state is shifted with less in the SRX state compared to controls
|
|
• tamoxifen treated mice show no cardiac hypertrophy in response to transaortic constriction induced pressure overload
• however, changes on protein expression induced by pressure overload in tamoxifen treated mice are similar to controls
|
|
• in tamoxifen treated mice the ratio of myosin in the SRX state to that in the DRX state is shifted with less in the SRX state compared to controls
|
|
• tamoxifen treated mice show no cardiac hypertrophy in response to transaortic constriction induced pressure overload
• however, changes on protein expression induced by pressure overload in tamoxifen treated mice are similar to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• no gross abnormalities in cardiac morphology or function
|
|
• healthy, without gross abnormalities
|
|
• viable
|
|
• increased cardiac hypertrophy and greater increase in heart weight to body weight (HW/BW) and tibia length (HW/TL) and lung weight to body weight (LW/BW) ratios and cardiomyocyte cross-sectional area 4 weeks after aortic banding
• increased extent of cardiac interstitial and perivascular fibrosis 4 weeks after aortic banding
• more cardiac ventricular dilation (increased left ventricle end-systolic and end-diastolic dimension) and greater decrease of fractional shortening 4 weeks after aortic banding
|
|
• fertile
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• cardiac dysfunction is reduced following ischemia/reperfusion injury
• decrease in adverse cardiac remodeling (interstitial fibrosis) following ischemia/reperfusion injury
• decrease in mitochondrial damage following ischemia/reperfusion injury
|
|
|
• following ischemia/reperfusion injury
|
|
|
• resistance to ischemia/reperfusion induced injury in cardiac cells
• ischemia/reperfusion induced increase in tethering of mitochondria and lysosomes is reduced
|
|
|
• cardiac dysfunction is reduced following ischemia/reperfusion injury
• decrease in adverse cardiac remodeling (interstitial fibrosis) following ischemia/reperfusion injury
• decrease in mitochondrial damage following ischemia/reperfusion injury
|
|
|
• following ischemia/reperfusion injury
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• cardiac dysfunction is increased following ischemia/reperfusion injury
• increase in adverse cardiac remodeling (interstitial fibrosis) following ischemia/reperfusion injury
• increase in mitochondrial damage following ischemia/reperfusion injury
|
|
|
• following ischemia/reperfusion injury
|
|
|
• decreased distance and increased length of mitochondria-lysosome contacts
|
|
|
• increased susceptibility to ischemia/reperfusion induced injury in cardiac cells
• ischemia/reperfusion induced increase in tethering of mitochondria and lysosomes is exacerbated
|
|
|
• cardiac dysfunction is increased following ischemia/reperfusion injury
• increase in adverse cardiac remodeling (interstitial fibrosis) following ischemia/reperfusion injury
• increase in mitochondrial damage following ischemia/reperfusion injury
|
|
|
• following ischemia/reperfusion injury
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice do not survive longer than 3 weeks after knockout initiation by tamoxifen (TAM) feeding
|
|
• after 3 weeks of TAM feeding, heart left ventricles (LVs) display disrupted intercalated discs with markedly reduced junctional proteins
• LVs exhibit patchy, weak N-cadherin (adherens junctions/area composita) and Connexin-43 (gap junctions) signals, suggesting altered cell-cell junctions
|
|
• after 3 weeks of TAM feeding, heart LVs exhibit more disorganized myofibrils than control LVs
• however, LVs display parallel lines of alpha-actinin staining, indicating that Z-lines of sarcomeres are intact
|
|
• after 3 weeks of TAM feeding, hearts display thinning of the ventricular walls
|
|
• after 3 weeks of TAM feeding
|
|
• after 3 weeks of TAM feeding
|
|
• after 3 weeks of TAM feeding, hearts display pronounced dilation of the left (LV) and right (RV) ventricle chambers
|
|
• after 3 weeks of TAM feeding
|
|
• after 3 weeks of TAM feeding
|
|
• after 3 weeks of TAM feeding, the LV myocardium is fibrotic with large inclusions of collagen protein in cardiomyocyte-free regions
|
|
• TAM-fed mice develop progressive left ventricular systolic dysfunction culminating in dilated cardiomyopathy and heart failure
• failing hearts exhibit gene expression changes similar to those observed in human dilated cardiomyopathy
|
|
• after 3 weeks of TAM feeding, all hearts are dilated, esp. at systole, and show severely decreased ventricular contractility with 6% FS (fractional shortening) versus 29% FS in controls
|
|
• after 2 weeks of TAM feeding, hearts show a trend of reduced left ventricular function and marked dilation, reflecting compromised contractility
|
|
• after 3 weeks of TAM feeding, ejection fraction (EF) and fractional shortening (FS) values are significantly decreased while values of LV volume at diastole and at systole are markedly increased
• however, LV contractile parameters are normal prior to TAM feeding as well as during the first week of TAM feeding
|
|
• after 3 weeks of TAM feeding, mice exhibit heart failure characterized by disrupted myofibril organization, defective intercalated disc structure, and widespread fibrosis
|
|
• after 3 weeks of TAM feeding, heart left ventricles (LVs) display disrupted intercalated discs with markedly reduced junctional proteins
• LVs exhibit patchy, weak N-cadherin (adherens junctions/area composita) and Connexin-43 (gap junctions) signals, suggesting altered cell-cell junctions
|
|
• after 3 weeks of TAM feeding, heart LVs exhibit more disorganized myofibrils than control LVs
• however, LVs display parallel lines of alpha-actinin staining, indicating that Z-lines of sarcomeres are intact
|
|
• TAM-fed mice develop progressive left ventricular systolic dysfunction culminating in dilated cardiomyopathy and heart failure
• failing hearts exhibit gene expression changes similar to those observed in human dilated cardiomyopathy
|
|
• after 3 weeks of TAM feeding, all hearts are dilated, esp. at systole, and show severely decreased ventricular contractility with 6% FS (fractional shortening) versus 29% FS in controls
|
|
• after 2 weeks of TAM feeding, hearts show a trend of reduced left ventricular function and marked dilation, reflecting compromised contractility
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| dilated cardiomyopathy | DOID:12930 |
OMIM:PS115200 |
J:338311 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mutants treated with tamoxifen at 8-9 weeks of age to induce Cre-mediated recombination die within 2 weeks of tamoxifen injection
|
|
• cardiomyocyte cytoplasm of tamoxifen treated mutants appears pale in patchy areas and contains variably prominent numbers of pink granules; focally abundant mitochondria correlate with the pink granules
• in some myocytes of tamoxifen treated mutants, aggregates of proliferating membranes of the sarcoplasmic reticulum are seen
• however, sarcomeres and Z-lines appear normal
|
|
• mutants treated with tamoxifen exhibit myocyte hypertrophy with enlarged, irregular myocyte nuclei
|
|
• thinning of the left ventricular wall after treatment with tamoxifen
|
|
• dilation of the left ventricle after treatment with tamoxifen
|
|
• rare degenerating myocytes and focal areas of mild interstitial fibrosis are seen in mutants treated with tamoxifen
|
|
• mutants treated with tamoxifen exhibit cardiac dysfunction in both systolic and diastolic parameters
|
|
• mutants treated with tamoxifen at 8-9 weeks of age to induce Cre-mediated recombination develop dilated cardiomyopathy
|
|
• peak early diastolic filling velocity is decreased by more than 30% in mutants treated with tamoxifen
|
|
• systolic function of mutants treated with tamoxifen exhibits a 50% or greater decrease in peak aortic flow velocity and both mean and peak acceleration
|
|
• isovolumic relaxation time is prolonged by more than 50% in mutants treated with tamoxifen
|
|
• standard deviation of RR intervals is increased 5-fold after tamoxifen administration
|
|
• at 4 days after the last day of tamoxifen administration, mice show 2:1 atrioventricular block
|
|
• progressive lengthening of the PR interval is seen beginning 2 days after the last day of tamoxifen administration
|
|
• widening of the QRS complex is seen beginning 2 days after the last day of tamoxifen administration
|
|
• cardiomyocyte cytoplasm of tamoxifen treated mutants appears pale in patchy areas and contains variably prominent numbers of pink granules; focally abundant mitochondria correlate with the pink granules
• in some myocytes of tamoxifen treated mutants, aggregates of proliferating membranes of the sarcoplasmic reticulum are seen
• however, sarcomeres and Z-lines appear normal
|
|
• mutants treated with tamoxifen exhibit myocyte hypertrophy with enlarged, irregular myocyte nuclei
|
|
• mutants treated with tamoxifen at 8-9 weeks of age to induce Cre-mediated recombination develop dilated cardiomyopathy
|
|
• systolic function of mutants treated with tamoxifen exhibits a 50% or greater decrease in peak aortic flow velocity and both mean and peak acceleration
|
|
• isovolumic relaxation time is prolonged by more than 50% in mutants treated with tamoxifen
|
|
• rare degenerating myocytes and focal areas of mild interstitial fibrosis are seen in mutants treated with tamoxifen
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| myotonic dystrophy type 1 | DOID:11722 |
OMIM:160900 |
J:127391 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in tamoxifen treated mice
|
|
• in tamoxifen treated mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• subcellular disorganization, with accumulation of vacuoles, mitochondria showing diversity in size, profoundly disrupted alignment, and a rounder and more densely packed appearance after tamoxifen treatment
• loss of mitochondrial cristae and smaller average mitochondria size after tamoxifen treatment
|
|
• distorted and wavy myofiber architecture 4 weeks after tamoxifen treatment
• mitochondrial deformities accompanied by electron-dense material are present after tamoxifen treatment
|
|
• elevated mitochondrial iron content but not heme levels 4 weeks after tamoxifen treatment
|
|
• 8 weeks after tamoxifen treatment
|
|
• increased left ventricular diastolic diameter at 8 weeks after tamoxifen treatment
|
|
• 8 weeks after tamoxifen treatment
|
|
• elevated lipid peroxidation and reactive oxygen species after tamoxifen treatment
|
|
• as early as 4 weeks after tamoxifen treatment
|
|
• reduced heart pump function as measured by fractional shortening and ejection fraction 4 and 8 weeks after tamoxifen treatment
• decreased strength of contraction (dP/dtmax) at 8 weeks after tamoxifen treatment
|
|
• decreased relaxation (dP/dtmin) at 8 weeks after tamoxifen treatment
|
|
• lower end systolic pressure at 8 weeks after tamoxifen treatment
|
|
• mild after tamoxifen treatment
|
|
• elevated mitochondrial iron content but not heme levels 4 weeks after tamoxifen treatment
|
|
• distorted and wavy myofiber architecture 4 weeks after tamoxifen treatment
• mitochondrial deformities accompanied by electron-dense material are present after tamoxifen treatment
|
|
• reduced heart pump function as measured by fractional shortening and ejection fraction 4 and 8 weeks after tamoxifen treatment
• decreased strength of contraction (dP/dtmax) at 8 weeks after tamoxifen treatment
|
|
• decreased relaxation (dP/dtmin) at 8 weeks after tamoxifen treatment
|
|
• mild after tamoxifen treatment
|
|
• 8 weeks after tamoxifen treatment
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• the volume of the atrioventricular node is reduced by about a third compared to controls 8 weeks after cre induction
|
|
• sinus node tachycardia is noted in about 17% of mice that have had cre expression induced
• sinus bradycardia is observed in about a third of the mice that have had cre expression induced
• long term monitoring of mice indicates a general increase in heart rate in the weeks after induction of cre
|
|
• the prolongation of the PR interval is a hallmark of atrioventricular block
• partial failure of AV conduction (25%) or total dissociation of atrial and ventricular rhythms (37.5%) occurs by 4 weeks after cre induction
• half of the mice have accelerated junctional rhythms that originate in the AV node
• not all the excitations successfully traverse the AV node at slower heart rates (i.e. increased Wenckebach periodity)
• dye-coupling experiments reveals leakiness between cardiomyocytes starting three weeks after cre induction
|
|
• mice have a prolonged PR-interval after induction of cre expression
• the length of the interval increases the longer after induction of cre
• by 4 weeks after induction of cre, the length of the interval has more than doubled
|
|
• the volume of the atrioventricular node is reduced by about a third compared to controls 8 weeks after cre induction
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• aggravated high-fat diet induced myocardial hypertrophy
|
|
• aggravated high-fat diet induced enlargement of the ventricular cavities
|
|
• aggravated high-fat diet induced cardiac fibrosis
|
|
• aggravated high-fat diet induced reduction in fractional shortening and ejection fraction
|
|
• aggravated diabetic cardiomyopathy on a high fat diet compared to diet matched controls
|
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• expression analysis indicates insulin resistance on a high fat diet
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• aggravated oxidative stress injury in response to a high fat diet compared to diet matched controls
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• aggravated high-fat diet induced myocardial hypertrophy
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• aggravated high-fat diet induced myocardial hypertrophy
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• aggravated high-fat diet induced reduction in fractional shortening and ejection fraction
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• aggravated diabetic cardiomyopathy on a high fat diet compared to diet matched controls
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• reduced number of microvessels form 2 weeks after transverse aortic constriction
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• attenuated development of hypertrophy as a result of transverse aortic restriction
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• impaired cardiac function
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• tamoxifen treated mice do not die prematurely
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| N |
• tamoxifen treated mice do not develop seizures
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Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 12/10/2024 MGI 6.24 |
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