Overexpression of P104L mutant caveolin-3 in mice led to hypertrophic cardiomyopathy, enhanced basal contractility, and increased endothelial nitric oxide synthase activity.
Does overexpression of P104L mutant caveolin-3 alter cardiac contractility and architecture in mice?
Loss of caveolin-3 function and subsequent moderate increase in eNOS activity results in hypertrophic cardiomyopathy in a transgenic mouse model.
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.
Yutaka Ohsawa (Tue,) conducted a other in Hypertrophic cardiomyopathy. P104L mutant caveolin-3 overexpression was evaluated on Biochemical and cardiac parameters. Overexpression of P104L mutant caveolin-3 in mice led to hypertrophic cardiomyopathy, enhanced basal contractility, and increased endothelial nitric oxide synthase activity.