Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity
Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity
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DOI：
10.1093/hmg/ddh014
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发表时间：
2004-01-15
影响因子：
3.5
通讯作者：
Sunada, Y
中科院分区：
文献类型：
--
作者：
Ohsawa, Y;Toko, H;Sunada, Y
内源性一氧化氮合酶（NOS）对心脏收缩力和结构的影响一直存在争议。NOS在心肌肥厚中的作用最近已被研究证实，这些研究表明，在组成型NOS （cNOS）敲除小鼠中，肥厚性心肌病（HCM）的收缩力发生了改变。Caveolin-3是所有NOS亚型的强抑制剂，在肌层小窝微域中表达，并在体内与心肌细胞内皮型一氧化氮合酶（eNOS）和骨骼肌细胞神经元型一氧化氮合酶（nNOS）结合。本研究对常染色体显性肢带肌营养不良（LGMD1C）模型P104L突变型caveolin-3转基因小鼠的生化和心脏参数进行了表征。转基因小鼠心脏表现为HCM、基础收缩力增强、左心室舒张末期直径减小、小洞蛋白-3蛋白缺失和细胞质定位错误。令人惊讶的是，心肌显示了eNOS催化活性的激活，但没有增加所有NOS亚型的表达。这些数据表明，eNOS活性的适度增加与小窝蛋白-3的缺失相关，可导致HCM。
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.