MD2蛋白在肥胖诱导心肌损伤中的作用和机制研究

Obesity is becoming a global disease in both children and adults. It is associated with numerous complications such as heart disease. Inflammation is a major pathological process in myocardial injury induced by obesity, the underlying mechanism of hyperlipidemia (free fatty acids) induced myocarditis however is not very well understood. Myeloid differentiation-2 (MD2), an important accessory protein of TLR4, mediates LPS-TLR4 induced acute inflammatory response. It is reported that TLR4 signaling plays an important role in obesity-induced myocarditis and cardiomyopathy, and it is not clear whether MD2 participates this process. There is no report on the relation between MD2 and obesity cardiomyopathy. In high fat diet (HFD) induced obese rats, we found that orally given MD2 small molecular inhibitor, CB69, obviously attenuated cardiomyopathy, along with the reduction of myocarditis response. These results indicate that MD2 maybe involved in the process of obesity-induced myocarditis and cardiomyopathy. We will illustrate the molecular mechanism of FFA activated myocarditis response by directly binding to MD2 and the role of MD2 in the process of obesity-induced cardiomyopathy in the cellular, molecular, and animal levels by using MD2 knockout mice, MD2 specific inhibitor, and RNA interference technique. This project will provide a new target for the treatment of obesity-induced cardiomyocytes.

肥胖可以导致多种并发症，包括心脏病变。炎症是肥胖诱导心肌损伤过程中的重要病理过程，但高血脂（游离脂肪酸）诱导心肌炎症发生的机制尚不清晰。髓样分化蛋白-2（MD2）是介导内毒素LPS激活TLR4急性炎症反应的重要辅助蛋白。研究显示TLR4信号通路在肥胖诱导心肌炎症和损伤的过程中起重要作用，但MD2是否参与和介导该过程尚不清楚，目前尚无MD2与肥胖性心肌损伤相关的报道。本实验室前期工作发现了口服MD2特异性小分子抑制剂CB69在高脂饮食诱导的肥胖大鼠中可以显著缓解心肌病变，并伴随着心肌炎症反应的下降，提示MD2可能介导了高血脂诱导的心肌炎症反应和心肌损伤。本项目中，我们拟利用MD2基因敲除小鼠、特异性抑制剂和RNA干扰等技术，从细胞、分子和动物三个层面，阐明FFA通过直接结合MD2激活心肌炎症反应的分子机制，明确MD2介导肥胖性心肌损伤的作用和机制。本项目将为肥胖性心肌损伤的防治提供新的靶点。

肥胖可以导致多种并发症，包括心脏病变。炎症是肥胖诱导心肌损伤过程中的重要病理过程，但高血脂（游离脂肪酸）诱导心肌炎症发生的机制尚不清晰。髓样分化蛋白-2（MD2）是介导内毒素LPS激活TLR4急性炎症反应的重要辅助蛋白。研究显示TLR4信号通路在肥胖诱导心肌炎症和损伤的过程中起重要作用，但MD2是否参与和介导该过程尚不清楚，目前尚无MD2与肥胖性心肌损伤相关的报道。本实验室前期工作发现了口服MD2特异性小分子抑制剂L6H9在高脂饮食诱导的肥胖大鼠中可以显著缓解心肌病变，并伴随着心肌炎症反应的下降，提示MD2可能介导了高血脂诱导的心肌炎症反应和心肌损伤。本项目中，我们在体外阐明了MD2小分子抑制剂L6H9抑制PA诱导的心肌细胞炎症反应和细胞损伤的药理药效和作用机制、通过多种分子生物学手段阐明了PA的直接作用靶点是MD2而不是TLR4且L6H9能够抑制PA与MD2蛋白的结合、在体内通过构建多种动物模型阐明了MD2小分子抑制剂L6H9及MD2基因敲除对肥胖诱导的心脏损伤和炎症反应的影响。本项目的实施为肥胖性心肌损伤的防治提供新的靶点和候选药物。