Hyperglycemia-induced overexpression of PHLPP1 compromised the cardioprotective effect of ischemic postconditioning via modulating the Akt/Mst1 pathway signalling.
Hyperglycemia-induced overexpression of PHLPP1 compromised the cardioprotective effect of ischemic postconditioning via modulating the Akt/Mst1 pathway signalling.
复制标题
高血糖诱导的 PHLPP1 过度表达通过调节 Akt/Mst1 信号通路损害缺血后处理的心脏保护作用。
作者：
高素敏;邱云;蒙钰铭;贾亚娟;郎雪梅;赵红梅;丁涟沭;孙虹;王婷婷
目的缺血后处理(IPostC)可减轻心肌缺血/再灌注(IR)损伤，但在糖尿病时这种保护作用消失。富含亮氨酸的重复蛋白磷酸酶1(PHLPP1)能够使Akt失活。我们先前的研究发现PHLPP1在糖尿病心脏中表达上调。我们推测，在糖尿病动物模型中，PHLPP1的过度表达可能阻碍了IPostC对心肌损伤的减轻。方法与结果非糖尿病组和糖尿病组小鼠脑缺血45min，再灌注2 h后加或不加IPostC。H9c2细胞暴露于正常或高糖环境中，低氧4h，复氧4h，加或不加低氧后处理(HPostC)。IpostC可减轻非糖尿病小鼠缺血后脑梗塞、细胞凋亡、肌酸激酶同工酶MB和氧化应激，同时增加p-Akt，降低PHLPP1和p-Mst1的表达，但对糖尿病小鼠无影响。PHLPP1基因敲除或Mst1抑制剂可减轻正常葡萄糖引起的H9c2细胞缺氧/复氧(HR)损伤，但这种作用可被PI3K/Akt抑制剂阻断。HpostC可减轻HR诱导的H9c2细胞损伤和氧化应激，同时增加p-Akt，降低PHLPP1和p-Mst1的表达，而不是高糖。此外，HPostC联合PHLPP1基因敲除或单独使用PHLPP1基因敲除可减少高糖暴露下H9c2细胞的死亡和氧化应激，这一点可被PI3K/Akt抑制剂阻止。结论IPostC部分通过PHLPP1/Akt/Mst1信号通路对心肌缺血再灌注损伤具有保护作用，该通路的异常可能是糖尿病IPostC心肌保护功能丧失的原因之一。
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.