支链氨基酸介导的能量代谢障碍在糖尿病心肌损伤中的作用及机制

Metabolic dysfunction is an independent risk factor for myocardial injury. However, numerous clinical studies have demonstrated glucose per se as a therapeutic target dose not improve the outcome in decreasing the cardiovascular complications. our recent studies have demonstrated that glucose-lipid metabolic disorder results in systemic BCAA catabolic disorders in obesity/diabetic mice (Diabetes, 2015); Conversely, BCAA catabolic disorders results in systemic glucose-lipid metabolic disorder(EBioMedicine, 2016). Surprisingly, our preliminary experimental results have clearly shown that chronic accumulation of BCAAs in a mouse model of impaired BCAA catabolism (PP2cm knockout) suppressed disrupted mitochondrial pyruvate utilization through inhibition of pyruvate dehydrogenase complex (PDH) activity and sensitized the heart to ischemic injury. Therefore, using pharmacological interventions and genetic animal models, our present project aims: 1) to reveal the causal link between BCAA related myopcadial injury and inhibition of PDH activity; if so, further to elucidate the molecular mechanisms by which posttranslational protein modification modulates the activity of PDH; 3) importantly, to explore effective pharmacological and genetic interventions to restore BCAA metabolism deregulation and metabolic dysfunction, thus providing a novel and promising therapeutic strategy for the prevention and treatment of metabolic disorder and myocardial injury in inviduals with T2DM.

代谢紊乱是心肌损伤的独立危险因素,但以糖、脂代谢为干预靶点的治疗措施效果不佳。我们前期研究证明,糖尿病动物出现以支链氨基酸(BCAA)堆积为特征的氨基酸代谢紊乱(Diabetes, 2015);而基因敲除所致BCAA代谢障碍动物继发全身糖脂代谢紊乱及器官损伤(EBioMedicine, 2016)。最新预实验发现，BCAA代谢紊乱小鼠心肌线粒体能量代谢调控关键分子丙酮酸脱氢酶(PDH)活性降低,缺血损伤加重。本课题结合基因干预模式动物与细胞分子手段,揭示PDH活性降低与BCAA代谢紊乱所致心肌损伤的因果关系;阐明PDH翻译后修饰与葡萄糖利用障碍能量代谢紊乱的内在联系; 确证切断糖脂与BCAA代谢紊乱互为因果的恶性循环及其导致的心肌能量代谢紊乱对糖尿病心肌的保护作用。为糖尿病心肌损伤提供新的分子机制，为从以干预BCAA代谢紊乱为切入点，预防和治疗糖尿病心肌代谢重构与心脏损伤提供新的治疗靶点。

糖、脂代谢紊乱是2型糖尿病（T2DM）损害心血管系统的主要肇事者，但T2DM即使接受强化降糖、降脂治疗仍残留较高心血管事件风险，这说明“糖、脂损伤学说”在指导T2DM心血管疾病防治仍有局限性。与糖、脂并列为三大营养物质的氨基酸代谢在T2DM和心血管损伤中的作用和机制仍不明晰。本项目发现亮氨酸、异亮氨酸和缬氨酸等支链氨基酸（BCAA）分解代谢障碍与异常蓄积是T2DM和缺血心肌损伤的共有代谢特征。病理浓度BCAA持续活化氨基酸感知信号mTORC1诱导Akt2泛素化降解导致T2DM胰岛素抵抗与糖脂代谢障碍（Diabetes, 2020），也通过上调PPARα促进心肌细胞糖-脂代谢转换，进而加重心肌细胞脂毒性并恶化心肌/缺血再灌注损伤（Theranostics, 2020）。不仅直接损伤心肌，BCAA异常蓄积通过BCAA-mTORC1-H3K9me3这一代谢物-信号转导-表观遗传修饰轴诱导移植进入缺血心肌微环境的间充质干细胞（MSCs）出现“老-死”表型，抑制其定植、存活和心肌修复作用（STTT, 2022）。此外，本项目还发现了代谢器官分泌的鸢尾素、CTRP9、胆汁酸和棕色脂肪组织外泌体等生物活性物质调节心肌损伤或MSCs心肌修复作用（Circ Res, 2019 封面文章; Adv Sci, 2022a; Adv Sci, 2022b 封面文章; Circ Res, 2022 当期述评）。上述工作证实，BCAA分解代谢障碍和异常蓄积是造成T2DM和缺血心肌损伤的关键致病因素，改善BCAA分解代谢和异常蓄积是实现“糖-心同治”新策略，这有力地支持了T2DM和心肌损伤的“氨基酸损伤学说”，提示靶向氨基酸代谢可望使T2DM和心血管疾病患者在降糖、降脂治疗的基础上进一步获益。