糖尿病心肌缺血/再灌注易损性增加的新机制：线粒体蛋白磷酸酶2C下调导致的支链氨基酸代谢异常

Diabetic patients with increased vulnerability of diabetic hearts to ischemic/reperfusion (I/R) injury, which can not be fully explained by “toxic” hyperglycemia. Diabetes not only reveal disturbed glucose and lipid metabolism, but also have abnormal protein metabolism. Studies have linked disturbed BCAA catabolism with diabetes mellitus and abnormal BCAA catabolism can lead to neuronal cells death. However, whether disturbed BCAA catabolism enhances diabetic heart to I/R injury is unknown. PP2Cm is a key molecular which regulates cell survival, development and BCAA catabolism. We found that down-regulated PP2Cm contributed to abnormal BCAA catabolism in diabetes mellitus and PP2Cm was significantly reduced in diabetic heart. But, whether reduced PP2Cm increases diabetic myocardial I/R injury and the underlying molecular mechanisms are unclear. Therefore, this study were to determine whether disturbed BCAA catabolism and down-regulated PP2Cm expression contribute to the increased vulnerability of diabetic hearts to I/R injury and the underlying molecular mechanisms. The present research provides a new explanation of enhanced diabetic myocardial I/R injury and promising therapeutic strategy for diabetic cardiovascular complications.

糖尿病患者心肌缺血/再灌注损伤显著增加，但高糖“毒性”并不能完全解释该现象。糖尿病患者不仅糖脂代谢紊乱，蛋白质代谢也存在异常。研究发现，糖尿病患者及动物支链氨基酸（BCAA）代谢异常，BCAA 代谢异常能够导致神经细胞死亡。但是，BCAA 代谢异常是否参与糖尿病心肌缺血/再灌注易损性增加尚不清楚。线粒体蛋白磷酸酶 2C（PP2Cm）是调节细胞生存、发育及 BCAA 代谢的重要分子。我们发现，PP2Cm 表达下调是糖尿病 BCAA 代谢异常的原因（Diabetes，2015），糖尿病小鼠心肌中 PP2Cm 蛋白表达显著下调。然而，PP2Cm 下调是否导致糖尿病心肌缺血/再灌注损伤增加及机制未见报道。据此，本课题拟证实：BCAA 代谢异常、 PP2Cm 下调增加糖尿病心肌缺血/再灌注损伤和其分子机制。该研究最终为糖尿病心肌易损性增加提供全新的解释，也为治疗糖尿病心血管并发症提供了全新的策略。

糖尿病状态下支链氨基酸（branched chain amino acids，BCAA）BCAA 代谢异常，其血浆中 BCAA 及BCKA含量显著增加。但是， BCAA 代谢异常是否导致糖尿病心肌/缺血再灌注易损性增加及其机制还不清楚。本研究首次探讨了BCAA代谢障碍增加缺血诱导的糖尿心肌损伤，同时首次报道了PP2Cm及线粒体氧化应激在BCAA心肌损伤中的作用。过表达PP2Cm及BT2治疗减轻糖尿病小鼠心肌缺血/再灌注损伤，其机制是PP2Cm导致BCAA代谢障碍及氧化应激损伤。过表达PP2Cm、BT2治疗纠正BCAA代谢、及采用MnTBAP抗氧化治疗能够减轻小鼠心肌缺血/再灌注损伤。本研究提示纠正PP2Cm介导的BCAA代谢异常及氧化损伤可以减轻糖尿病心肌缺血/再灌注损伤。