Title of article :
Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy
Author/Authors :
Tatiana Tsoutsman، نويسنده , , Jessica Chung، نويسنده , , Alessandra Doolan، نويسنده , , Lan Nguyen، نويسنده , , Iwan A. Williams، نويسنده , , Emily Tu، نويسنده , , Lien Lam، نويسنده , , Charles G. Bailey، نويسنده , , John E.J. Rasko، نويسنده , , David G. Allen، نويسنده , , Christopher Semsarian، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2006
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.
Keywords :
Mice , Calcium , Troponin I gene , hypertrophy , cardiomyopathy
Journal title :
Journal of Molecular and Cellular Cardiology
Journal title :
Journal of Molecular and Cellular Cardiology