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  • Title: Blockage of PHLPP1 protects against myocardial ischemia/reperfusion injury in diabetic mice via activation of STAT3 signaling.
    Author: Gao S, Qiu Y, Meng Y, Jia Y, Lang X, Zhao H, Sun H, Zhang J, Ding L.
    Journal: J Bioenerg Biomembr; 2023 Oct; 55(5):325-339. PubMed ID: 37584737.
    Abstract:
    Diabetes can exacerbate myocardial ischemia/reperfusion (IR) injury. However, the sensitivity to IR injury and the underlying mechanisms in diabetic hearts remain unclear. Inhibition of PH domain leucine-rich repeating protein phosphatase (PHLPP1) could reduce myocardial IR injury, our previous study demonstrated that the expression of PHLPP1 was upregulated in diabetic myocardial IR model. Thus, this study aimed to investigate the mechanism of PHLPP1 in diabetic myocardial IR injury. Nondiabetic and diabetic C57BL/6 mice underwent 45 min of coronary artery occlusion followed by 2 h of reperfusion. Male C57BL/6 mice were injected with streptozotocin for five consecutive days to establish a diabetes model. H9c2 cells were exposed to normal or high glucose and subjected to 4 h of hypoxia followed by 4 h of reoxygenation. Diabetes or hyperglycemia increased postischemic infarct size, cellular injury, release of creatine kinase-MB, apoptosis, and oxidative stress, while exacerbating mitochondrial dysfunction. This was accompanied by enhanced expression of PHLPP1 and decreased levels of p-STAT3 and p-Akt. These effects were counteracted by PHLPP1 knockdown. Moreover, PHLPP1 knockdown resulted in an increase in mitochondrial translocation of p-STAT3 Ser727 and nuclear translocation of p-STAT3 Tyr705 and p-STAT3 Ser727. However, the effect of PHLPP1 knockdown in reducing posthypoxic cellular damage was nullified by either Stattic or LY294002. Additionally, a co-immunoprecipitation assay indicated a direct interaction between PHLPP1 and p-STAT3 Ser727, but not p-STAT3 Tyr705. The abnormal expression of PHLPP1 plays a significant role in exacerbating myocardial IR injury in diabetic mice. Knockdown of PHLPP1 to activate the STAT3 signaling pathway may represent a novel strategy for alleviating myocardial IR injury in diabetes.
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