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Human Molecular Genetics Advance Access originally published online on November 25, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 2 151-157
DOI: 10.1093/hmg/ddh014

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

Yutaka Ohsawa1, Haruhiro Toko2, Masashi Katsura3, Kazue Morimoto1, Haruki Yamada1, Yaeko Ichikawa1, Tatsufumi Murakami1, Seitaro Ohkuma3, Issei Komuro2 and Yoshihide Sunada1,*

1Division of Neurology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki-City, Okayama 701-0192, Japan, 2Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan and 3Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki-City, Okayama 701-0192, Japan

Received July 8, 2003; Accepted November 11, 2003

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.

* To whom correspondence should be addressed: Tel: +81 864621111; Fax: +81 864621199; Email: ysunada{at}med.kawasaki-m.ac.jp


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