Vasile Vlad C, Edwards William D, Ommen Steve R, Ackerman Michael J
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Biochem Biophys Res Commun. 2006 Oct 20;349(2):709-15. doi: 10.1016/j.bbrc.2006.08.106. Epub 2006 Aug 24.
Mutations in the cardiac-specific insert of vinculin, metavinculin, rarely cause hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Subsequently, a missense mutation in the ubiquitously expressed vinculin was discovered in a patient with obstructive HCM. Microscopic examination of both myectomy specimens from patients bearing genetic defects in metavinculin and vinculin showed a marked reduction of vinculin/metavinculin expression in the intercalated disc, but normal expression in the Z-disc. Given that distinct functional domains were altered by the metavinculin and vinculin mutations, we hypothesized that the intercalated disc-specific reduction of vinculin may stem from left ventricular tract obstruction in general rather than rarely observed perturbations in VCL-encoded vinculin. To test this hypothesis, we examined the localization of vinculin/metavinculin in hypertrophied human heart tissue from patients with cardiovascular conditions associated with obstruction and hemodynamic overload using an immunohistochemistry approach. Tissue specimens derived from patients with obstructive HCM and aortic stenosis (AS) showed a universal defect of vinculin/metavinculin expression in the intercalated disc but preserved expression in the cardiac Z-disc, whereas tissue specimens derived from patients with either DCM, hypertensive heart disease (HTN), or pulmonary hypertension (PHTN) exhibited normal expression of vinculin/metavinculin in both the Z- and the intercalated disc despite being associated with hypertrophy. Results of this study suggest that cardiac hypertrophy may be associated with different expression of the marker vinculin/metavinculin depending on the underlying pathophysiology; hemodynamic overload may not affect the localization whereas obstructive disease substantially reduces the expression of vinculin preferentially in the intercalated disc.
纽蛋白特异性插入片段（间纽蛋白）的突变很少导致肥厚型心肌病（HCM）和扩张型心肌病（DCM）。随后，在一名梗阻性HCM患者中发现了普遍表达的纽蛋白中的一个错义突变。对携带间纽蛋白和纽蛋白基因缺陷患者的心肌切除标本进行显微镜检查发现，闰盘中纽蛋白/间纽蛋白的表达明显减少，但Z盘中表达正常。鉴于间纽蛋白和纽蛋白突变改变了不同的功能结构域，我们推测闰盘特异性的纽蛋白减少可能一般源于左心室流出道梗阻，而非罕见的VCL编码的纽蛋白扰动。为验证这一假设，我们采用免疫组织化学方法检查了来自患有与梗阻和血流动力学超负荷相关心血管疾病患者的肥厚型人类心脏组织中纽蛋白/间纽蛋白的定位。来自梗阻性HCM和主动脉瓣狭窄（AS）患者的组织标本显示闰盘中纽蛋白/间纽蛋白表达普遍缺陷，但心脏Z盘中表达保留，而来自DCM、高血压性心脏病（HTN）或肺动脉高压（PHTN）患者的组织标本尽管与肥厚相关，但在Z盘和闰盘中纽蛋白/间纽蛋白均表达正常。本研究结果表明，心脏肥大可能因潜在病理生理学不同而与标记物纽蛋白/间纽蛋白的不同表达相关；血流动力学超负荷可能不影响其定位，而梗阻性疾病会优先显著降低闰盘中纽蛋白的表达。
