PK2/PKRs在糖尿病心肌病中的作用及机制研究

Diabetic cardiomyopathy(DCM),which is caused by diabetes mellitus with the main feature of cardiac structure and function disorder has become a major cause of mortality in diabetic patients,but the pathogenesis of DCM has not been completely elucidated.PK2 is a kind of multi-functional secreted proteins.It has been reported that PK2 has the function of stimulating vessel-like formation in H5V endothelial cell and protecting against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyocytes.In addition,in human end-stage failing heart samples,the level of PK2 is significantly decreased.However,the role of PK2 in cardiovascular is far from full research.The first discovery of our studies shown that the PK2 expression decreased in diabetic mice heart and PK2 prevented high glucose-induced cardiomyocyte injury,which was accompanied with the activation of Akt.It suggests that PK2 may play a critical role in triggering the development of DCM.This study aims to determine the relationship between PK2 & PK2 receptors(PKRs) and myocardial injury,and demonstrate the effectiveness of the administration of PK2 on improving the diabetes-induced cardiomyopathy in vivo.And further,we study the expression of PK2 and PKRs under high glucose condition,and clarify the protecting effects and molecular mechanism of PK2 on high glucose-induced myocardial injury through inhibition of PKRs in vitro.Aiming to enrich DCM pathogenesis and seek new targets for prevention the DCM has important theoretical and practical significance.

糖尿病心肌病（DCM）是由糖尿病引起的一种心脏结构和功能障碍性疾病，成为糖尿病患者的主要死因，但具体发病机制未明。PK2是一种多功能分泌蛋白，研究表明PK2可促进H5V细胞的血管样结构生成、抑制过氧化氢所致的H9c2细胞氧化损伤，而且在心衰末期患者心脏中表达下降。然而，PK2对心血管的作用研究仅限于此。我们前期预研究首次发现：PK2在糖尿病小鼠心脏中表达下降；PK2逆转高糖诱导的心肌细胞损伤，增加磷酸化Akt的表达，提示PK2可能在DCM的发生发展中起到重要的作用。本项目拟在整体水平研究PK2和PK2受体（PKRs）与DCM的关联性，证实给予PK2改善糖尿病小鼠心肌损伤的作用及初步机制；进一步在细胞水平研究高糖对PK2和PKRs的影响，通过体外抑制PKRs表达，阐明PK2对高糖诱导心肌细胞损伤的保护作用及分子机制。本研究对于丰富DCM发病机制、寻找防治DCM新靶点具有重要的理论和实践意义。