HMGB1通过引起肌浆网Ryanodine受体钙漏流致糖尿病心肌病发生的作用和机制研究

Diabetic cardiomyopathy (DCM) is a kind of heart disease caused by abnormal glucose metabolism, which is manifested as cardiac systolic and diastolic dysfunction and myocardial remodeling, including cardiac hypertrophy and fibrosis. It is well established that High mobility group protein B1 (HMGB1) increases significantly in DCM and is closely related to the development of DCM. However the underlying mechanisms remains largely unknown. Our previous work demonstrated that HMGB1 increased the activity of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR), leading to enhancement of SR Ca2+ leakage. A recent research has link SR Ca2+ leak to cardiac remodeling in ischemic-reperfusion heart injury. Therefore, we proposed that SR Ca2+ leakage contributed to decreased myocardial contractility, myocardial hypertrophy and cardiac fibrotic remodeling induced by increased HMGB1 in DCM. We will apply multiple advanced technologies, such as manipulation of gene expression, confocal Ca2+ imaging of local Ca2+ signal (Ca2+ sparks) in cardiomyocytes and producing DCM animal model, to testify our hypothesis and investigate the possible underlying mechanisms. Furthermore, we will explore the therapeutic effect of inhibition of SR calcium leakage with RyR stabilizer, JTV519, on the treatment of diabetic cardiomyopathy induced by HMGB1. Through these efforts, we hope to enrich our understanding of the mechanism of DCM and provide new therapeutic strategies for the treatment of DCM.

糖尿病心肌病（DCM）是由糖代谢异常所致的一种心脏病，表现为心肌舒缩功能受损和心肌重构。高迁移率族蛋白B1（HMGB1）在DCM时明显升高并与DCM的发生发展密切相关，其机制尚待阐明。我们以往工作发现HMGB1增加肌浆网（SR）ryanodine receptor活性。在此，我们提出以下设想：DCM时增加的HMGB1通过引起SR钙漏流造成（1）心肌收缩力降低；（2）心肌肥大性改变；（3）心脏纤维化重构，从而引起糖尿病心肌病发生。抑制SR钙漏流可抑制HMGB1引起的糖尿病心肌病的发生。本项目拟利用分子生物学、confocal钙显微成像、DCM动物模型等技术查明HMGB1-介导的SR钙漏流在DCM中的作用和机制。还将探讨抑制SR钙漏流药物（JTV519）对DCM的治疗作用。旨在阐明DCM发生的机制，为治疗提供新思路。

糖尿病心肌病(DCM)是由糖代谢异常所致的一种心脏病，早期表现为无症状的舒张功能障碍，最终发展为有症状的充血性心力衰竭，收缩功能受损。高迁移率族蛋白B1 (high mobility group box l，HMGB1)是一高度保守的DNA结合蛋白，由坏死细胞被动释放或由免疫细胞主动释放。HMGB1是否在糖尿病心肌是起作用仍未知。本研究利用分子生物学、confocal钙显微成像、DCM动物模型等技术发现高糖高脂刺激时HMGB1显著升高，而HMGB1激活Toll样受体4（Toll-like receptor 4，TLR4）-氧自由基（ROS）信号通路，增加心肌细胞RyR分子的氧化应激，致舒张期RyR活性增强，增加钙火花的发放，增加钙漏流，引起心肌肥大和纤维化的机制，从而造成心功能障碍。在动物模型中HMGB1加重糖尿病小鼠心肌纤维化，心肌肥大加重，证实对抗SR钙漏流药物JTV-519和虎杖苷以及扩张微血管药物导升明在对抗DCM时均具有良好防治作用，这为糖尿病心肌病的临床治疗提供新思路。