PP2Cm overexpression alleviates MI/R injury mediated by a BCAA catabolism defect and oxidative stress in diabetic mice
PP2Cm overexpression alleviates MI/R injury mediated by a BCAA catabolism defect and oxidative stress in diabetic mice
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PP2Cm 过表达可减轻 T2DM 小鼠中由 BCAA 分解代谢缺陷和氧化损伤介导的 MI/R 损伤
DOI：
10.1016/j.ejphar.2019.172796
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发表时间：
2020-01-05
影响因子：
5
通讯作者：
Tao, Ling
中科院分区：
文献类型：
--
作者：
Lian, Kun;Guo, Xiong;Tao, Ling
糖尿病患者对心肌缺血再灌注（MI/R）损伤敏感。在糖尿病期间，支链氨基酸（BCAA）催化剂缺陷，线粒体磷酸酶2C（PP 2Cm）表达减少。本研究旨在阐明糖尿病小鼠心肌梗死/再灌注损伤中PP 2Cm下调与BCAA catalysts缺陷的关系。PP 2Cm在糖尿病小鼠心脏中显著下调。过表达PP 2Cm的糖尿病小鼠MI/R后心功能改善，心肌梗死面积减少，细胞凋亡减少。在糖尿病小鼠中，心脏BCAA及其代谢产物支链酮酸（BCKA）水平和p-BCKDE 1 α（BCKA脱氢酶的E1亚基）/BCKDE 1 α比值升高，而BCKD活性降低。用BT 2（一种BCKD激酶（BDK）抑制剂）治疗MI/R损伤的糖尿病小鼠，减轻了BCAA catalysts缺陷，并改善了心脏功能，同时减少了细胞凋亡。PP 2Cm过表达可减轻BCAA代谢缺陷和MI/R损伤。同样，MnTBAP改善氧化应激和MI/R损伤。在模拟缺血/再灌注（SI/R）损伤下，BCKA处理H9 C2细胞显著降低细胞活力，增加LDH释放和凋亡。BT 2和MnTBAP处理可减轻这些影响。这些结果表明，PP 2Cm直接介导糖尿病MI/R后观察到的BCAA catalysts缺陷和氧化应激。PP 2Cm的过表达通过减少BCAA的释放和氧化应激来减轻MI/R损伤。
Diabetic patients are sensitive to myocardial ischemia-reperfusion (MI/R) injury. During diabetes, branched-chain amino acid (BCAA) catabolism is defective and mitochondrial phosphatase 2C (PP2Cm) expression is reduced. This study aims to elucidate the relationship between PP2Cm downregulation and BCAA catabolism defect in diabetic mice against MI/R injury. PP2Cm was significantly downregulated in hearts of diabetic mice. The cardiac function was improved and the myocardial infarct size and apoptosis were decreased in diabetic mice overexpressing PP2Cm after MI/R. In diabetic mice, the cardiac BCAA and its metabolites branched-chain keto-acids (BCKA) levels, and p-BCKDE1 alpha (E1 subunit of BCKA dehydrogenase)/BCKDE1 alpha ratio were increased while the BCKD activity was decreased. Treatment of diabetic mice subjected to MI/R injury with BT2, a BCKD kinase (BDK) inhibitor, alleviated the BCAA catabolism defect, and improved the cardiac function alongside reduced apoptosis. PP2Cm overexpression alleviated the BCAA catabolism defect and MI/R injury. Similarly, MnTBAP ameliorated the oxidative stress and MI/R injury. BCKA treatment of H9C2 cells under simulated ischemia/reperfusion (SI/R) injury significantly decreased cell viability and increased LDH release and apoptosis. These effects were alleviated by BT2 and MnTBAP treatments. These results suggested that PP2Cm directly mediates the BCAA catabolism defect and oxidative stress observed after MI/R in diabetes. Overexpression of PP2Cm alleviates MI/R injury by reducing the catabolism of BCAA and oxidative stress.