Cardiovascular drugs and therapy · 2022
Hyperglycemia-Induced Overexpression of PH Domain Leucine-Rich Repeat Protein Phosphatase 1 (PHLPP1) Compromises the Cardioprotective Effect of Ischemic Postconditioning Via Modulation of the Akt/Mst1 Pathway Signaling.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Qiu Yun, Meng Yuming, Jia Yajuan, Lang Xuemei, Zhao Hongmei, Ding Lianshu, Wang Tingting, Sun Hong, Gao Sumin
Аннотация
PURPOSE: Ischemic postconditioning (IPostC) alleviates myocardial ischemia/reperfusion (IR) injury, but the protective effect is lost during diabetes. PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is able to inactivate Akt. Our previous study found that PHLPP1 expression was upregulated in diabetic hearts. We presumed that the attenuation of myocardial injury by IPostC might be hindered by PHLPP1 overexpression in diabetic animals.
METHODS AND RESULTS: Nondiabetic and diabetic mice were subjected to 45 min of ischemia followed by 2 h of reperfusion with or without IPostC. H9c2 cells were exposed to normal or high glucose and were subjected to 4 h of hypoxia followed by 4 h of reoxygenation with or without hypoxic postconditioning (HPostC). IPostC attenuated postischemic infarction, apoptosis, creatine kinase-MB, and oxidative stress, which were accompanied by increased p-Akt and decreased PHLPP1 expression and p-Mst1 in nondiabetic but not in diabetic mice. PHLPP1 knockdown or an Mst1 inhibitor reduced hypoxia/reoxygenation (HR)-induced cardiomyocyte damage in H9c2 cells exposed to normal glucose, but the effect was abolished by a PI3K/Akt inhibitor. HPostC attenuated HR-induced cardiomyocyte injury and oxidative stress accompanied by 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 signaling, and abnormalities in this pathway may be responsible for the loss of IPostC cardioprotection in diabetes.
METHODS AND RESULTS: Nondiabetic and diabetic mice were subjected to 45 min of ischemia followed by 2 h of reperfusion with or without IPostC. H9c2 cells were exposed to normal or high glucose and were subjected to 4 h of hypoxia followed by 4 h of reoxygenation with or without hypoxic postconditioning (HPostC). IPostC attenuated postischemic infarction, apoptosis, creatine kinase-MB, and oxidative stress, which were accompanied by increased p-Akt and decreased PHLPP1 expression and p-Mst1 in nondiabetic but not in diabetic mice. PHLPP1 knockdown or an Mst1 inhibitor reduced hypoxia/reoxygenation (HR)-induced cardiomyocyte damage in H9c2 cells exposed to normal glucose, but the effect was abolished by a PI3K/Akt inhibitor. HPostC attenuated HR-induced cardiomyocyte injury and oxidative stress accompanied by 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 signaling, and abnormalities in this pathway may be responsible for the loss of IPostC cardioprotection in diabetes.