title: Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Kawasaki Medical School, Kurashiki-City, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ohsawa
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.forename: Masashi
authors.initials: M
authors.lastname: Katsura
authors.forename: Kazue
authors.initials: K
authors.lastname: Morimoto
authors.forename: Haruki
authors.initials: H
authors.lastname: Yamada
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Tatsufumi
authors.initials: T
authors.lastname: Murakami
authors.forename: Seitaro
authors.initials: S
authors.lastname: Ohkuma
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Sunada
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D051244:Caveolin 3; D022461:Caveolins / Q000235:genetics* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III
chemical_list: C495548:Cav3 protein, mouse; D051244:Caveolin 3; D022461:Caveolins; C496320:NOS1 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse