缺血后处理(IPostC)对心肌缺血再灌注损伤具有保护作用，但是保护作用在糖尿病中消失，机制仍不清楚。PH结构域富含亮氨酸重复序列蛋白激酶1(PHLPP1)可灭活蛋白激酶B(Akt)而激活哺乳动物STE-20样激酶1(Mst1)，进而促进凋亡和抑制自噬。预实验发现IPostC降低PHLPP1的表达而提升Akt的活性和抑制Mst1的活性，减少细胞凋亡和增加细胞自噬，最终减轻心肌损伤，而以上作用在糖尿病中消失。预实验同时发现在糖尿病心肌中PHLPP1过度表达，导致Akt活性显著降低和Mst1活性增加，而通过下调PHLPP1的表达可减轻缺氧再复氧后高糖培养细胞的损伤。由此推测PHLPP1表达异常导致保护通路调节受损是IPostC对糖尿病心肌保护失敏感的关键。本课题拟采用多种实验技术，在整体和细胞水平阐明以上推论，为IPostC更好的应用于临床提供理论依据。

Ischemic postconditioning (IPostC) protects the heart from ischemia reperfusion (IR) injury. However, IPostC cardioprotection is lost in diabetic hearts and its mechanisms remain unclear. PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) suppresses protein kinase B (Akt) and in turn activates Ste20-like protein kinase (Mst1) to promote apoptosis and inhibit autophagy. Our pilot experiments revealed that IPostC exerted cardioprotection against myocardial IR injury via decreasing the expression of PHLPP1 to augment Akt activity and inhibit Mst1 activity to reduce apoptosis and increase autophagy; however, these effects were not present in the myocardium of diabetic mice. Our data also revealed that diabetes was concomitant with cardiac overexpression of PHLPP1, elevation of Mst1 activity, and reduction of Akt activity and that downregulation of PHLPP1 expression alleviates the hypoxia/reoxygenation-induced injury in H9c2 cells exposed to high glucose. Hence, we speculate that PHLPP1 signaling plays an important role in the IPostC-induced cardioprotection via modulating apoptosis and autophagy of myocardial cells and that the aberrant expression of PHLPP1 to impair the protective signaling is possibly the key role resulting in myocardial desensitization to IPostC in diabetic rodents. This project intends to employ multiple in vivo and in vitro experimental approaches to examine the aforementioned hypotheses. The resulting data may provide a mechanistic basis for the clinical application of IPostC in ischemic heart disease.