Role of STIM1 in cardiac hypertrophy and heart failure

描述(申请人提供)：在美国，心脏瓣膜或高血压性心脏病引起的压力超负荷导致的心肌肥厚是充血性心力衰竭的主要原因。虽然一定程度的心肌肥厚可以减少室壁压力，但心肌细胞内长时间的促肥厚信号是有害的，并导致心力衰竭的进展。心肌肥厚通常伴随着钙依赖的信号通路的激活和胎儿基因表达程序的重新诱导。在钙依赖的通路中，钙调神经磷酸酶-NFAT轴特别重要，因为它在心肌肥厚的早期被激活。在最近发表的一项研究中，我们报道了STIM1控制着一种新描述的成年肥厚心肌细胞的肌膜电流，该电流激活NFAT并进一步促进心肌肥厚。基质相互作用分子1(STIM1)是一种动态的跨膜内质网钙离子感受器，在许多细胞类型的钙离子库耗尽时激活质膜SOCE(存储操作的钙离子进入)通道。我们发现STIM1在控制药物诱导的SOCE的新生大鼠心室肌细胞(NRVMs)中表达升高。这种STIM1依赖的、药物诱导的SOCE在从对照心脏分离的成年心肌细胞中是边缘的。然而，在主动脉缩窄后出现代偿性心肌肥厚的成年大鼠分离的心肌细胞中，STIM1的表达和功能重新出现。在这些肥大的成年心肌细胞中，STIM1不仅控制SOCE，而且还控制一种内向整流的肌膜电流，这种电流发生在没有药物诱导的储备耗竭的情况下。有趣的是，在肥厚的情况下，肌浆网钙负荷并没有显著降低，这表明STIM1的激活也可以发生在钙储存不依赖的模式中。通过调控其表达，我们发现STIM1通过激活钙调神经磷酸酶NFAT促进心肌肥厚的发展。此外，我们还发现，在体外和体内，通过RNA干扰沉默STIM1可以阻止心肌肥厚的发生。我们现在建议表征参与STIM1激活的分子通路，并评估在心脏肥厚和心力衰竭的啮齿动物模型中沉默STIM1的生理后果。了解STIM1激活所涉及的特定信号通路的作用，并开发局部调节这些机制的方法，可能为心肌肥厚和心力衰竭的管理提供新的治疗方法。

DESCRIPTION (provided by applicant): Pressure overload-induced cardiac hypertrophy due to valvular or hypertensive heart disease is a major cause of congestive heart failure in the U.S. While some degree of cardiac hypertrophy reduces wall stress, prolonged pro-hypertrophic signaling within cardiomyocytes is detrimental and contributes to the progression to heart failure. Cardiac hypertrophy is typically accompanied by the activation of Ca2+-dependent signaling pathways and the re-induction of a fetal gene expression program. Among the Ca2+-dependent pathways, the calcineurin-NFAT axis is of particular importance because it is activated at early stages of cardiac hypertrophy. In a recently published study, we have reported that STIM1 controls a newly described sarcolemmal current in adult hypertrophied cardiomyocytes that activates NFAT and further promotes cardiac hypertrophy. Stromal interaction molecule 1 (STIM1) is a dynamic transmembrane endoplasmic reticulum calcium sensor that activates plasma membrane SOCE (Store Operated Calcium Entry) channels in response to Ca2+ store depletion in many cell types. We found that STIM1 expression is elevated in neonatal rat ventricular myocytes (NRVMs) where it controls drug-inducible SOCE. This STIM1-dependent, drug-inducible SOCE was marginal in adult cardiomyocytes isolated from control hearts. However, STIM1 expression and function re-emerge in cardiomyocytes isolated from adult rats that had developed compensated cardiac hypertrophy after aortic constriction. In these adult hypertrophied cardiomyocytes, STIM1 not only controls SOCE but also an inwardly rectifying sarcolemmal current that occurs in the absence of drug-induced store depletion. Interestingly, SR Ca2+ load was not significantly decreased in hypertrophic conditions suggesting STIM1 activation can also occur in a calcium- store independent mode. By manipulating its expression, we found that STIM1 promotes the development of cardiac hypertrophy through calcineurin-NFAT activation. In addition, we found that STIM1 silencing by RNA interference abrogates the development of cardiac hypertrophy both in vitro and in vivo. We now propose to characterize the molecular pathways involved in STIM1 activation and to evaluate the physiological consequences of silencing STIM1 in rodent models of cardiac hypertrophy and heart failure. Understanding the role of specific signaling pathways involved in STIM1 activation and developing approaches to local modulation of these mechanisms may provide novel therapeutic approaches for the management of cardiac hypertrophy and heart failure.