酮体β-羟丁酸介导支链氨基酸（BCAAs）代谢障碍加重糖尿病心肌缺血再灌注损伤的机制研究

糖尿病是心血管疾病主要的危险因素之一。糖尿病患者由于氧化应激、胰岛素抵抗以及一系列代谢综合征，导致心肌对缺血再灌注（I/R）损伤的敏感性增高。这种心肌"I/R 敏化"是糖尿病患者心肌缺血事件高发病率和高死亡率的重要原因，并且削弱了传统心肌保护措施的效能。本课题将从在体、离体动物和细胞水平，结合13C-NMR同位素分析、代谢组学、线粒体生物学、蛋白翻译后修饰等多个研究层面和技术，系统验证支链氨基酸（BCAAs）代谢障碍是糖尿病心肌I/R损伤敏化的关键靶点，揭示促进BCAAs代谢可提高心肌酮体β-羟丁酸的氧化利用，减少线粒体蛋白过度β-羟基丁酰化修饰，发挥糖尿病心肌保护作用。其中，抑制胰岛素抵抗，改善线粒体功能、氧化应激，以及维持线粒体钙稳态是主要保护环节。这种针对线粒体能量底物代谢的治疗方案有望从源头切断造成糖尿病心肌I/R损伤敏化的路径，为临床糖尿病心肌保护提供新的思路和药物作用靶点。

Diabetes mellitus is one of the major risk factors for cardiovascular disease. Because of oxidative stress, insulin resistance and metabolic syndrome, the diabetic heart is more sensitive to ischemia/reperfusion (I/R) injury, and thus the morbility and mortality of ischemic heart disease in diabetic patients are much higher as compared to non-diabetic patients. Traditional cardioprotective strategies have minimal or even no effect on diabetic heart. Based on previous findings, this application will use in vivo/vitro animal model, cell culture and multiple methods, such as 13C-NMR isotopomer analysis, targeted metabolomics, mitochondrial biology, protein post-translational modification, demonstrating that deficiency in branched-chain amino acids (BCAAs) catabolism is responsible for the I/R sensitive phenotype of diabetic heart. Promoting BCAAs catabolism is capable of improving ketone body β-hydroxybutyrate (βOHB) utilization and attenuating mitochondrial protein β-hydroxybutyrylation (Kbhb). This will ameliorate insulin resistance, improve mitochondrial function, suppress oxidative stress and maintain mitochondrial calcium homeostasis, which contribute to reducing I/R injury in diabetic heart. The strategy focusing on optimizing mitochondrial substrate utilization is a promising way to protect diabetic heart against I/R injury, which will provide new thought and novel therapeutic target for diabetic heart protection.