胰岛素生长因子-1受体对心肌钙库操纵性钙内流的调节及其在压力负荷心肌肥厚中的作用及机制研究

Pressure overload hypertrophy is one of the major risk factors for malignant arrhythmia and heart failure. It is an important factor of intracellular Ca2+ signaling abnormality to myocardial hypertrophy under pressure overload. Store-operated Ca2+ entry (SOCE) is the key mechanism to control intracellular Ca2+ signaling. The core machinery of SOCE includes stromal interacting molecule-1 (STIM1) and plasma membrane Ca2+ release-activated Ca2+ channel pore forming subunit 1 (Orai1) proteins. At present, it has been confirmed that SOCE mediates the onset of pathological myocardial hypertrophy, but the specific mechanism is not clear. It is well known IGF-1 signaling is closely associated with heart function. IGF-1 regulates several cellular processes including metabolism, apoptosis, autophagy, aging and growth. However, it is unclear whether the IGF-1 signaling is associated with SOCE. Recently, we found that IGF-1 may be a regulator of cardiac SOCE, and low expression of IGF-1R delayed the onset of cardiac hypertrophy induced by pressure overload. These ideas would disclose the role and mechanism of IGF-1R on myocardial remodeling, thus having an important significance for the theoretical basis on clinical treatment strategies of IGF-1R as one therapeutic means, and a new target for the prevention and treatment for pressure overload heart diseases.

压力负荷心肌肥厚是致恶性心律失常和心衰的主要危险因素之一，细胞内钙信号异常是致压力负荷心肌肥厚的重要因素，钙库操纵性钙内流(Store-operated Ca2+ entry, SOCE)是调控细胞内钙信号的主要机制。SOCE由间质相互作用分子1(STIM1)和钙激活释放钙通道分子1(Orai1)蛋白组成，目前对于SOCE介导病理性心肥厚的具体调控机制尚不明确。胰岛素生长因子-1(Insulin growth factor-1, IGF-1)与心脏功能关系密切，调控心肌代谢、凋亡、自噬、老化等。IGF-1/IGF-1R信号通路与SOCE是否有关联目前不清楚。最近，课题组发现IGF-1R可能是调节心肌SOCE的作用因子，低表达IGF-1R延缓压力负荷心肌肥厚。这些观点的阐明，将为揭示IGF-1R在心肌肥厚中的作用及机制提供理论基础，为负荷型心脏病的防治提供新靶点和治疗策略，具有重要的意义。

背景：心肌肥厚的病理生理机制复杂，涉及到多种细胞学事件的发生发展，并出现细胞内钙信号转导异常。在非兴奋性细胞和病理性心肌细胞，外钙内流致内钙库耗竭钙通道开放（SOCE）介导。已证实，胰岛素生长因子1/胰岛素生长因子受体（IGF-1/IGF-1R）系统参与调控心脏能量代谢、心肌细胞生长、凋亡和自噬等，且IGF1R活化能够激活细胞内酪氨酸激酶，进而促发磷酸化级联反应、磷脂信号和基因转录。既往研究发现1）乳鼠心室肌细胞中，心肌钙库耗竭开放SOCE；2）病理性心肌肥大的心肌中，IGF-1R磷酸化水平表达升高。.主要研究内容：本项目主要系统地研究IGF-1R对心肌SOCE的生理性调节及作用机制，及其在病理性心肌肥大中的作用及机制，进一步揭示IGF-1R表达改变与肥厚性心肌病的关系，从而为心肌钙信号的调控和防治病理性心肌肥大提供新的理论基础。.重要结果：1）在HeLa细胞和乳鼠心室肌细胞（NRVMs）中，IGF-1R与SOCE的主要基质蛋白分子STIM1有相互作用和共定位，从而调节SOCE。2）IGF-1R的抑制剂OSI-906通过AMPK/SIRT3信号通路抑制血管紧张素II（Ang II）诱导的病理性心肌肥大、心肌纤维化、氧化应激与心肌炎症损伤；3）协助完成2项山东省中医药管理局课题：①地龙血管紧张素转化酶抑制肽防治高血压心脏重构的作用及机制；②松脂醇二葡萄糖苷对病理性心肌肥大的作用及机制。.意义：本研究首次揭示了心肌细胞中IGF-1R与STIM1具有相互作用的调控机制，及IGF-1R在病理性心肌肥厚中的作用及机制；目前还发发现，全身性IGF-1R敲除与肥厚性心肌病心衰密切相关。目前发表SCI论文1篇，另2篇论文分别在投稿中，培养研究生2人，青年教师2人。