Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity

• Published in: Human molecular genetics Vol. 13; no. 2; pp. 151 - 157
• Main Authors: Ohsawa, Yutaka, Toko, Haruhiro, Katsura, Masashi, Morimoto, Kazue, Yamada, Haruki, Ichikawa, Yaeko, Murakami, Tatsufumi, Ohkuma, Seitaro, Komuro, Issei, Sunada, Yoshihide
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.01.2004; Oxford Publishing Limited (England)
• Subjects: Animals; Biological and medical sciences; Cardiology. Vascular system; Cardiomyopathy, Hypertrophic - etiology; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - physiopathology; Caveolin 3; Caveolins - genetics; Caveolins - metabolism; Classical genetics, quantitative genetics, hybrids; Cytoplasm - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genetics of eukaryotes. Biological and molecular evolution; Heart; Human; Humans; limb-girdle muscular dystrophy; Medical sciences; Mice; Mice, Transgenic; Molecular and cellular biology; Mutation; Myocardial Contraction; Myocarditis. Cardiomyopathies; Myocardium - metabolism; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Enzyme; Rodentia; Contractility; Gene overexpression; Cardiovascular disease; Myocardial disease; Nitric-oxide synthase; Endothelium; Genetic disease; Vertebrata; Mammalia; Association; Mouse; Heart disease; Hypertrophic cardiomyopathy; Genetics; Oxidoreductases; Mutation
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddh014

The effect of endogenous nitric oxide synthase (NOS) on cardiac contractility and architecture has been a matter of debate. A role for NOS in cardiac hypertrophy has recently been demonstrated by studies which have shown hypertrophic cardiomyopathy (HCM) with altered contractility in constitutive NOS (cNOS) knockout mice. Caveolin-3, a strong inhibitor of all NOS isoforms, is expressed in sarcolemmal caveolae microdomains and binds to cNOS in vivo: endothelial nitric oxide synthase (eNOS) in cardiac myocytes and neuronal nitric oxide synthase (nNOS) in skeletal myocytes. The current study characterized the biochemical and cardiac parameters of P104L mutant caveolin-3 transgenic mice, a model of an autosomal dominant limb-girdle muscular dystrophy (LGMD1C). Transgenic mouse hearts demonstrated HCM, enhanced basal contractility, decreased left ventricular end diastolic diameter, and loss and cytoplasmic mislocalization of caveolin-3 protein. Surprisingly, cardiac muscle showed activation of eNOS catalytic activity without increased expression of all NOS isoforms. These data suggest that a moderate increase in eNOS activity associated with loss of caveolin-3 results in HCM.