冠状动脉微循环功能障碍直接限制心肌供血供氧、进而严重影响心血管疾病预后。既往研究发现心肌缺氧可以代偿性触发代谢适应性调节，而调节失代偿则导致心肌持续性损伤。冠脉微血管是直接感知心肌代谢的部位，但微血管如何启动和调节代谢适应性尚不明确。课题组前期在微血管障碍的心肌蛋白组中发现多种代谢限速酶出现差异性改变，伴线粒体Lon蛋白酶（LonP）表达下调；加用ATP敏感性钾通道（KATP）开放剂治疗微栓塞，可上调LonP、改善心肌代谢，故推测KATP/LonP可能参与微血管感知和心肌代谢调节。本课题拟构建差异性表达LonP的急性和慢性冠脉微血管损伤模型，质谱检测明确特异性代谢底物的变化，比色法检测代谢酶活性；同时加用KATP开放剂或阻断剂，明确KATP/LonP在微血管感知调节心肌代谢的分子机制；并在临床微循环障碍队列中明确KATP开放剂、代谢底物检测与心血管预后的关联，为冠脉微血管防治提供新的证据。

Coronary microvascular dysfunction plays a critical role in myocardial blood and oxygen supply, and deteriorates the prognosis of heart disease further. In previous studies, myocardial ischemia could initiate compensate cardiac metabolic flexibility, while the occurrence of decompensate regulation will result in persistent cardiac injury. Coronary micro-vessels are one of direct sensors to cardiac metabolism, however, it is still unknown how to initiate and regulate cardiac metabolic flexibility by micro vessels. In our pilot study, proteomics indicated the significant changes of critical metabolic rate-limiting enzyme in myocardium of coronary microvascular dysfunction. We also confirmed mitochondrial Lon protease (LonP) was decreased after coronary microembolization. After treated by cardiac ATP-sensitive potassium channels (KATP) opener (Nicorandil), both LonP and cardiac metabolism was improved. Therefore, we supposed that KATP and LonP participate cardiac metabolic flexibility regulation after coronary microvascular dysfunction. In this study, mice acute and chronic coronary microvascular dysfunction mice models with differential expression of LonP were developed. Then specific metabolites and metabolic rate-limiting enzyme were detected by mass spectrometer and colorimetric method respectively. KATP opener or blocker will be applied to elaborate the role and mechanism of signal KATP/LonP in metabolic regulation after microvascular dysfunction. Furthermore, we will also clarify the effect of KATP opener in coronary microvascular dysfunction cohort and the prediction role of specific metabolites in patients’ prognosis. Above all, these findings will provide novel evidence for clinical diagnosis and treatment of coronary microvascular dysfunction and relevant cardiac injury.