Role of STIM1 in cardiac hypertrophy and heart failure

STIM1 在心脏肥大和心力衰竭中的作用

• 批准号: 8459948
• 负责人: Jean Sebastien Hulot
• 金额: $ 40.34万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459948
• 关键词: Adult; Calcineurin; Calcineurin Pathway; Calcium; Cardiac; Cardiac Myocytes; Cell membrane; Cells; Complex; Congestive Heart Failure; Dependovirus; Development; Drug Controls; Endoplasmic Reticulum; Failure; Gene Expression; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; In Vitro; Ion Channel; Knockout Mice; Measurement; Mediating; Membrane Proteins; Modeling; Molecular; Muscle Cells; Nature; Neonatal; Pathway interactions; Pharmaceutical Preparations; Phosphoproteins; Phosphorylation; Physiological; Post-Translational Protein Processing; Property; Protein Kinase; Protein Kinase Inhibitors; Publishing; RNA Interference; Rattus; Recombinant adeno-associated virus (rAAV); Regulation; Reporting; Rodent; Rodent Model; Role; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction; Staging; Stimulus; Stress; Testing; Ventricular; Viral Vector; base; cell type; constriction; fetal; human STIM1 protein; hypertensive heart disease; in vivo; insight; mouse model; novel therapeutic intervention; overexpression; pressure; programs; protein kinase inhibitor; response; sensor; small hairpin RNA

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.

描述（由申请人提供）：在美国，由瓣膜性或高血压性心脏病引起的压力超载引起的心脏肥厚是充血性心力衰竭的主要原因。虽然某种程度的心脏肥厚减轻了壁压力，但心肌细胞内延长的促肥厚信号是有害的，并有助于心力衰竭的进展。心脏肥大通常伴随着Ca2+依赖性信号通路的激活和胎儿基因表达程序的重新诱导。在Ca2+依赖通路中，钙调磷酸酶- nfat轴是特别重要的，因为它在心脏肥大的早期阶段被激活。在最近发表的一项研究中，我们报道了STIM1在成人肥大心肌细胞中控制一种新描述的肌层电流，该电流激活NFAT并进一步促进心脏肥大。基质相互作用分子1 （STIM1）是一种动态的跨膜内质网钙传感器，它激活质膜SOCE（储存操作钙入口）通道，以响应许多细胞类型的Ca2+储存耗尽。我们发现STIM1表达在新生大鼠心室肌细胞（nrvm）中升高，其中它控制药物诱导的SOCE。这种依赖于stim1的药物诱导的SOCE在从对照心脏分离的成人心肌细胞中是边缘性的。然而，在主动脉收缩后发生代偿性心脏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。在这些成年肥大心肌细胞中，STIM1不仅控制SOCE，还控制在没有药物诱导的存储耗尽时发生的内向整流肌层电流。有趣的是，在肥厚的情况下，SR Ca2+负荷并没有显著降低，这表明STIM1激活也可能发生在钙储存独立的模式下。通过调控其表达，我们发现STIM1通过钙调磷酸酶- nfat激活促进心肌肥厚的发生。此外，我们发现通过RNA干扰使STIM1沉默可以在体外和体内消除心肌肥厚的发生。我们现在提出表征参与STIM1激活的分子途径，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。了解参与STIM1激活的特定信号通路的作用，并开发这些机制的局部调节方法，可能为心脏肥厚和心力衰竭的治疗提供新的治疗方法。