Critical role for stromal interaction molecule 1 in cardiac hypertrophy.
Critical role for stromal interaction molecule 1 in cardiac hypertrophy.
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DOI：
10.1161/circulationaha.111.031229
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发表时间：
2011-08-16
期刊：
影响因子：
37.8
通讯作者：
Engelhardt S
中科院分区：
文献类型：
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作者：
Hulot JS;Fauconnier J;Ramanujam D;Chaanine A;Aubart F;Sassi Y;Merkle S;Cazorla O;Ouillé A;Dupuis M;Hadri L;Jeong D;Mühlstedt S;Schmitt J;Braun A;Bénard L;Saliba Y;Laggerbauer B;Nieswandt B;Lacampagne A;Hajjar RJ;Lompré AM;Engelhardt S
心肌细胞（CM）不仅在兴奋-收缩偶联（ECC）中利用Ca 2+，而且作为促进例如心脏肥大的信号分子。在ECC期间发生的快速和大的Ca 2+波动的存在下，Ca 2+如何触发CM中的信号传导在很大程度上是不清楚的。一个潜在的途径是钙库操纵的钙离子进入（SOCE），这是一种需要基质相互作用分子1（STIM 1）的药物诱导的钙离子信号传导机制。SOCE也可以在心肌细胞中诱导，这促使我们在体外和体内研究STIM 1依赖的Ca 2+内流与心肌肥大的关系。与早期的报道一致，我们在新生大鼠心肌细胞中发现了药物诱导的SOCE，这依赖于STIM 1。虽然这种STIM 1依赖性，药物诱导的SOCE在从对照心脏分离的成年心肌细胞中仅是边缘性的，但在从腹主动脉缩窄后发生代偿性心脏肥大的成年大鼠分离的心肌细胞中显著增加。此外，我们检测到一个内向整流电流在肥大心肌细胞，发生在自然条件下（即在没有药物诱导的存储耗尽），并依赖于STIM 1。通过操纵其表达，STIM 1被发现是体外和体内成人心脏心肌细胞肥大的充分和必要条件。通过AAV 9介导的基因转移沉默Stim 1保护大鼠免受压力超负荷诱导的心脏肥大。STIM 1通过控制一种以前未被认识到的肌膜电流促进心肌肥大。
Cardiomyocytes (CM) utilize Ca2+ not only in excitation-contraction coupling (ECC), but also as a signaling molecule promoting for example cardiac hypertrophy. It is largely unclear how Ca2+ triggers signaling in CM in the presence of the rapid and large Ca2+ fluctuations that occur during ECC. A potential route is store-operated Ca2+ entry (SOCE), a drug-inducible mechanism for Ca2+ signaling that requires stromal interaction molecule 1 (STIM1). SOCE can also be induced in cardiomyocytes, which prompted us to study STIM1-dependent Ca2+-entry with respect to cardiac hypertrophy in vitro and in vivo. Consistent with earlier reports, we found drug-inducible SOCE in neonatal rat cardiomyocytes, which was dependent on STIM1. While this STIM1-dependent, drug-inducible SOCE was only marginal in adult cardiomyocytes isolated from control hearts, it significantly increased in cardiomyocytes isolated from adult rats that had developed compensated cardiac hypertrophy after abdominal aortic banding. Moreover, we detected an inwardly rectifying current in hypertrophic cardiomyocytes that occurs under native conditions (i.e. in the absence of drug-induced store depletion) and is dependent on STIM1. By manipulating its expression, STIM1 was found to be both sufficient and necessary for cardiomyocyte hypertrophy both in vitro and in the adult heart in vivo. Stim1 silencing by AAV9-mediated gene transfer protected rats from pressure overload-induced cardiac hypertrophy. STIM1 promotes cardiac hypertrophy by controlling a previously unrecognized sarcolemmal current.