Familial hypertrophic cardiomyopathy: functional variance among individual cardiomyocytes as a trigger of FHC-phenotype development
Familial hypertrophic cardiomyopathy: functional variance among individual cardiomyocytes as a trigger of FHC-phenotype development
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DOI：
10.3389/fphys.2014.00392
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发表时间：
2014-10-10
影响因子：
4
通讯作者：
Kraft, Theresia
中科院分区：
文献类型：
--
作者：
Brenner, Bernhard;Seebohm, Benjamin;Kraft, Theresia
家族性肥厚型心肌病（FHC）是最常见的遗传性心脏病。它与许多肌节蛋白甚至一些非肌节蛋白的许多突变有关。然而，到目前为止，没有共同的机制已被确定的许多不同的突变在不同的肌节和非肌节蛋白触发FHC表型的发展。在这里，我们显示了不同MYH 7突变在从正常到高度异常的力pCa关系中的差异，这是我们研究的所有突变的共同特征，而不同FHC突变的直接功能效应，例如，在力的产生、ATP酶或收缩系统的钙敏感性上，可以是相当不同的。M. FHC患者的比目鱼肌纤维伴随着突变型与野生型β-MyHC-mRNA的大的变化。初步结果显示，在单个心肌细胞中，突变型与野生型β-MyHC-mRNA的变化相似。我们讨论了我们以前提出的概念，β-MyHC和其他可能的肌节和非肌节蛋白质的不同突变可能会引发FHC表型的功能变异个体心肌细胞，导致心肌内的结构扭曲，导致细胞和肌原纤维紊乱。此外，扭曲可以激活心肌细胞和非心肌细胞中的牵张敏感性信号传导，已知其诱导具有间质纤维化和肥大的心脏重塑。这种机制将对预防FHC发展的治疗策略具有重要意义，例如，通过减少单个心肌细胞之间的功能不平衡或通过抑制它们触发引发重塑的信号通路。靶向增加或减少的收缩功能将需要选择性靶向突变体或野生型蛋白以减少功能失衡。
Familial hypertrophic cardiomyopathy (FHC) is the most frequent inherited cardiac disease. It has been related to numerous mutations in many sarcomeric and even some non-sarcomeric proteins. So far, however, no common mechanism has been identified by which the many different mutations in different sarcomeric and non-sarcomeric proteins trigger development of the FHC phenotype. Here we show for different MYH7 mutations variance in force pCa-relations from normal to highly abnormal as a feature common to all mutations we studied, while direct functional effects of the different FHC-mutations, e.g., on force generation, ATPase or calcium sensitivity of the contractile system, can be quite different. The functional variation among individual M. soleus fibers of FHC-patients is accompanied by large variation in mutant vs. wildtype beta-MyHC-mRNA. Preliminary results show a similar variation in mutant vs. wildtype beta-MyHC-mRNA among individual cardiomyocytes. We discuss our previously proposed concept as to how different mutations in the beta-MyHC and possibly other sarcomeric and non-sarcomeric proteins may initiate an FHC-phenotype by functional variation among individual cardiomyocytes that results in structural distortions within the myocardium, leading to cellular and myofibrillar disarray. In addition, distortions can activate stretch-sensitive signaling in cardiomyocytes and non-myocyte cells which is known to induce cardiac remodeling with interstitial fibrosis and hypertrophy. Such a mechanism will have major implications for therapeutic strategies to prevent FHC-development, e.g., by reducing functional imbalances among individual cardiomyocytes or by inhibition of their triggering of signaling paths initiating remodeling. Targeting increased or decreased contractile function would require selective targeting of mutant or wildtype protein to reduce functional imbalances.