丹酚酸A调控SIRT3/PKM2介导的糖代谢重编程抑制血管内皮细胞焦亡防治糖尿病动脉粥样硬化的研究

糖尿病动脉粥样硬化（DA）是糖尿病并发心血管病的主要原因和病理基础，糖尿病患者血管内皮细胞中发生了糖代谢重编程，以有氧糖酵解为能量主要来源，并诱发细胞损伤和炎症。以糖代谢紊乱和内皮细胞炎症为切入点，深入探讨DA的机制和防治具有重大的意义。前期研究发现，糖代谢重编程的关键酶-M2型丙酮酸激酶（PKM2）在小鼠AS斑块中高表达，阻止PKM2表达和入核可抑制内皮细胞焦亡。丹酚酸A具有抗糖尿病和动脉粥样硬化的作用，但其在防治DA中的作用及机制尚未明确。.本项目拟通过构建DA动物模型和高糖损伤的内皮细胞模型，并利用基因敲除技术、相关分子抑制剂或激活剂处理，深入探讨PKM2介导的糖代谢重编程调控内皮细胞焦亡的机制，阐明丹酚酸A通过激活SIRT3，促使PKM2去乙酰化，逆转PKM2四聚体-二聚体转换，抑制内皮细胞焦亡的作用。本项目旨在为DA的治疗提供新的思路，也为拓展丹酚酸A的临床应用提供实验基础。

Diabetic atherosclerosis (DA) is the main cause and pathological basis of diabetes complicated with cardiovascular diseases.Vascular endothelial cells in diabetic patients undergo glucose metabolism reprogramming and the aerobic glycolysis is their main source of energy, which induces cells injury and inflammation. Thus, taking glucose metabolism disorder and endothelial cell inflammation as entry points, it is of great significance to deeply explore the mechanism and prevention of DA. In previous studies, we found that M2 type pyruvate kinase (PKM2), the key enzyme of glucose metabolism reprogramming is highly expressed in AS plaques of ApoE deficiency mouse, and arresting PKM2 expression and nuclear import can inhibit pyroptosis in endothelial cells. Salvianolic acid A has anti-diabetic and anti-atherosclerotic effects, but its role and mechanism in preventing and treating DA are not yet clear..In this project, we plan to construct DA animal models and endothelial cell models with high glucose injury, and some methods such as gene knockout technology, treating with inhibitors or activators of key molecular were used to further explore the role and mechanism of PKM2-mediated glucose metabolism reprogramming in regulating endothelial pyroptosis, and to clarify that salvianolic acid A promotes the deacetylation of PKM2 by activating SIRT3, reverses the PKM2 tetramer-dimer conversion, and inhibits endothelial cell pyroptosis. In addition, this project will provide new ideas for the treatment of DA, and also provide an experimental basis for the expansion of the clinical application of salvianolic acid A.