Hyperglycemia-induced Overexpression of PHLPP1 Compromised the Cardioprotective Effect of Ischemic Postconditioning via Modulating the Akt/Mst1 Pathway Signalling.

Purpose Ischemic postconditioning (IPostC) alleviates myocardial ischemia/reperfusion (IR) injury, but the protective effect is lost in diabetes. PH domain leucine-rich repeat protein phosphatase1 (PHLPP1) is able to inactivate Akt. Our previous study found that PHLPP1 expression was upregulated in diabetic heart. We presumed that attenuation of myocardial injury by IPostC might be hindered by PHLPP1 overexpression in diabetic animals. Methods and results Non-diabetic and diabetic mice were subjected to 45 min ischemia followed by 2 h reperfusion with or without IPostC. H9c2 cells were exposed to normal or high glucose and subjected to 4 h hypoxia followed by 4 h reoxygenation with or without hypoxic postconditioning (HPostC). IPostC attenuated postischemic infarction, apoptosis, creatine kinase-MB and oxidative stress, accompanied with increased p-Akt as well as decreased PHLPP1 expression and p-Mst1 in non-diabetic but not in diabetic mice. PHLPP1 knockdown or Mst1 inhibitor reduced hypoxia/reoxygenation (HR)-induced cardiomyocyte damage in H9c2 cells exposed to normal glucose, but the effect was abolished by PI3K/Akt inhibitor. HPostC attenuated HR-induced cardiomyocyte injury and oxidative stress accompanied with increased p-Akt as well as decreased PHLPP1 expression and p-Mst1 in H9c2 cells exposed to normal glucose but not high glucose. In addition, HPostC in combination with PHLPP1 knockdown or PHLPP1 knockdown alone reduced cell death and oxidative stress in H9c2 cells exposed to high glucose, which was hindered by PI3K/Akt inhibitor. Conclusion IPostC prevented myocardial IR injury partly through PHLPP1/Akt/Mst1 signalling, and the abnormality of this pathway may be responsible for the loss of IPostC cardioprotection in diabetes.