有氧运动联合Hmgcs2抑制疗法在改善小鼠脂毒性心肌病中的作用及机制研究

Lipotoxic cardiomyopathy is one of the complications of obesity and diabetes.we used expression spectrum chip technology to find that the increase of Hmgcs2 in the heart of mice with early lipotoxic cardiomyopathy was the most obvious.Inhibition of calpain prevented the increase of Hmgcs2 stimulated by palmitate in cardiomyocytes.8 weeks of swimming exercise can improve the cardiac function,decrease the expression of Hmgcs2, inhibit calpain activity ,and up-regulate JPH2 expression in Lipotoxic cardiomyopathy mice.In addition, inhibition of calpain activity can also reduce the expression of Hmgcs2 and increase the level of JPH2 protein in the lipotoxic heart.We will compare the effects of different aerobic exercises (water platform or swimming) on the expression of Hmgcs2,explore the role of "exercise combined with Hmgcs2 inhibition" in improving cardiac lipotoxicity and lipotoxic cardiomyopathy,and to study the mechanism of Hmgcs2.Immunofluorescence staining and immunoprecipitation were used to determine the relationship between Hmgcs2 and JPH2, calpain, cyp11a1 or other molecules.Our results may help to provide new targets for the prevention and treatment of lipotoxic cardiomyopathy, to enriche the theory of exercise rehabilitation for metabolic diseases.

脂毒性心肌病是肥胖和糖尿病患者的并发症之一。我们应用表达谱芯片技术，首次发现，早期脂毒性心肌病小鼠心脏中Hmgcs2升高最明显；棕榈酸诱导的心肌细胞中Hmgcs2表达升高，特异性抑制Hmgcs2表达后，心肌细胞凋亡减少。8周游泳运动改善脂毒性心肌病小鼠心脏功能，同时降低Hmgcs2基因表达，减少calpain酶活性，增加JPH2蛋白表达。进一步研究表明，脂毒性心脏中抑制calpain活性也能降低Hmgcs2表达，增加JPH2蛋白水平。本项目将比较不同有氧运动方式（水中跑台或游泳）对Hmgcs2表达的影响，接着探索“运动联合Hmgcs2抑制疗法”在改善脂毒性心肌病的作用，并深入研究Hmgcs2的参与机制；应用免疫荧光染色法与免疫共沉淀技术，确定Hmgcs2与JPH2、calpain及cyp11a1等分子的调节或互作关系。项目完成为脂毒性心肌病的防治提供新靶点，丰富“代谢性疾病运动康复理论”。

肥胖和糖尿病及其并发症是世界性公共卫生问题，威胁全人类健康。肥胖因素联系的心肌病，与糖尿病型心肌病类似，发生心肌纤维化，心肌肥厚和心脏功能紊乱，被称为脂毒性心肌病。本项目以Hmgcs2为研究核心分子，主要内容分为两大部分：第一，研究有氧运动抑制Hmgcs2在改善小鼠脂毒性心肌病中的作用；第二，阐明受运动抑制的Hmgcs2在缓解心脏脂毒性和减少心肌细胞脂毒性损伤的作用机制。我们研究阐明运动通过上调miR-344g-5p靶向抑制Hmgcs2，是运动改善脂毒性心肌病的重要机制之一，项目成果为后续脂毒性心肌病药物研发、营养补充策略提供重要的实验依据。