Relaxin-3调控NLRP3炎症体抑制糖尿病心肌病心肌损伤的研究

Relaxin-3 is a active peptide which inhibits myocardial fibrosis. Our previous study found that there was no obvious difference in the relaxin-3 levels between healthy controls and patients with diabetes, however, exogenous relaxin-3 can suppress the apoptosis of neonatal rat ventricular myocytes and NLRP3 inflammasome expression of cardiac fibroblasts induced by high glucose. To sum up, we proposed that P2X7R and ROS activated in myocardium in diabetic cardiomyopathy, activated the NLRP3 inflammasome and released IL-1ß and IL-18, then lead to myocardial injury inhibited by relaxin-3. We will construct diabetic cardiomyopathy rats model, the apoptosis of myocardial cell and the fibrosis of cardiac fibroblasts model induced by high glucose, then we observed that whether exogenous relaxin-3 inhibited expression of P2X7R and ROS, activation of NLRP3 inflammasome, release of inflammatory cytokines in myocardial cells and fibroblasts during diabetic cardiomyopathy. This project will provide new targets in the mechanism and treatment of diabetic cardiomyopathy relieved by relaxin-3.

Relaxin-3是一种很强抗心肌纤维化的内源性活性肽。我们前期发现“和健康对照组比较，糖尿病病人血浆中relaxin-3水平没有明显变化，而外源性relaxin-3能抑制高糖诱导的乳鼠心肌细胞凋亡和心脏成纤维细胞NLRP3炎症体表达”。综上所述，我们提出科学假说“糖尿病心肌病时心肌组织中P2X7R和ROS的激活，活化NLRP3炎症体，释放IL-1ß和IL-18等细胞因子，导致心肌损伤，而relaxin-3通过抑制NLRP3炎症体活化抑制糖尿病心肌病心肌损伤”。本课题拟通过糖尿病心肌病大鼠以及高糖诱导的心肌细胞凋亡和心脏成纤维细胞纤维化模型为研究对象，外源性给予relaxin-3后，观察心肌P2X7R和ROS表达、NLRP3炎症体活化和炎症因子释放以及心肌损伤情况，阐明relaxin-3减轻心肌损伤的新机制，从而为relaxin-3防治糖尿病心肌病心肌损伤的提供新理论依据。

Relaxin-3是一种很强抗心肌纤维化的内源性活性肽。我们前期发现“和健康对照组比较，糖尿病病人血浆中relaxin-3水平没有明显变化，而外源性人重组relaxin-3（human recombinant relaxin-3，H3 relaxin）能抑制高糖诱导的乳鼠心肌细胞凋亡和心脏成纤维细胞NLRP3炎症体表达”。本研究中，我们制备STZ诱导的糖尿病心肌病的大鼠模型，给予外源性H3 relaxin，观察H3 relaxin对于糖尿病心肌病大鼠心肌纤维化、凋亡和NLRP3炎症体的影响。我们发现STZ注射后4周和8周心肌凋亡和纤维化标志物蛋白水平明显升高，STZ诱导的糖尿病大鼠心肌NLRP3炎症体蛋白表达增加并激活。与糖尿病心肌病组比较，H3 relaxin治疗能减低凋亡和纤维化相关蛋白标志物表达。除此之外，H3 relaxin能抑制NLRP3炎症体相关的蛋白表达和激活，抑制STZ诱导的糖尿病大鼠血浆中IL-1β 和 IL-18 的升高。另外，体外高糖诱导乳鼠心脏成纤维细胞纤维化模型，我们发现H3 relaxin能调控NLRP3炎症体活化而抑制高糖诱导的成纤维细胞胶原合成，并且发现调控NLRP3炎症体活化的上游机制与ROS和P2X7R激活相关。