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Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy
- Source :
-
Journal of Molecular & Cellular Cardiology . Oct2006, Vol. 41 Issue 4, p623-632. 10p. - Publication Year :
- 2006
-
Abstract
- Abstract: Gene mutations in cardiac troponin I (cTnI) account for up to 5% of genotyped families with familial hypertrophic cardiomyopathy (FHC). Little is known about how cTnI mutations cause disease. Five lines of transgenic mice were generated which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), in a cardiac-specific manner. Mice were compared to transgenic mice that overexpress normal cTnI (cTnI-wt) and non-transgenic littermates (NTG). cTnI-G203S mice developed all the characteristic features of FHC by age 21 weeks. Left ventricular hypertrophy was observed on echocardiography (1.25±0.05 mm vs. 0.86±0.02 mm in cTnI-wt, P <0.01), associated with a significant 4-fold increase in RNA markers of hypertrophy, ANF and BNP. Myocyte hypertrophy, myofiber disarray and interstitial fibrosis were observed in cTnI-G203S mice. Expression of the cTnI-G203S mutation in neonatal cardiomyocytes resulted in a significant increase in myocyte volume, and reduced interactions with both troponins T and C. Ca2+ cycling was abnormal in adult cardiomyocytes extracted from cTnI-G203S mice, with a prolonged decay constant in Ca2+ transients and a reduced decay constant in response to caffeine treatment. Mice with the cTnI-G203S gene mutation develop all the phenotypic features of human FHC. The cTnI-G203S mutation disrupts interactions with partner proteins, and results in intracellular Ca2+ dysregulation early in life, suggesting a pathogenic role in development of FHC. [Copyright &y& Elsevier]
- Subjects :
- *CARDIOMYOPATHIES
*HYPERTROPHY
*PATHOLOGY
*CALCIUM
Subjects
Details
- Language :
- English
- ISSN :
- 00222828
- Volume :
- 41
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Journal of Molecular & Cellular Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 22419194
- Full Text :
- https://doi.org/10.1016/j.yjmcc.2006.07.016