基于ASMase/NLRP3炎性小体的非经典炎症通路研究糖尿病性血管损伤机制及药物治疗

胰岛素抵抗是2型糖尿病前期血管损伤的关键因素，研究其调控机制是解决2型糖尿病早期血管并发症的重要策略。酸性神经鞘磷脂酶（ASMase）通过水解质膜表面的鞘磷脂，产生神经酞胺，参与生物信号传导，我们多年的研究探讨ASMase在心血管疾病中的病理作用。本项目利用ASMase基因敲除小鼠建立冠状动脉内皮细胞胰岛素抵抗模型，或者提取2型糖尿病患者主动脉内皮细胞，研究ASMase调控NLRP3炎性小体，通过其非经典炎症途径高迁移率组蛋白B1（HMGB1）诱导胰岛素抵抗的机制。同时分析ASMase/NLRP3炎性小体构成的信号通路参与2型糖尿病小鼠和患者血管内皮病理变化与功能损伤。最后，基于ASMase/NLRP3炎性小体通路，评估大黄提取的天然产物大精酸对2型糖尿病血管损伤的改善作用。本项目揭示血管内皮细胞胰岛素抵抗的新调控机理，对防治2型糖尿病早期血管并发症提供新的药物作用靶点。

Insulin resistance is regarded as a critical mechanism in vascular lesion as early 2 type diabetes, which is an important strategy in treatment of in vascular complication in early 2 type diabetes. ASMase (acid sphingomyelinase) hydrolyzes sphingomyelin to produce ceramide, which is involved biological signal conduction; our study focuses on the roles and mechanism of ASMase in the pathogenesis of cardiovascular disease. Coronary arterial endothelial cells from wild-type and ASMase gene knockout mice and aorta endothelial cells from 2 type diabetic patients are used to establish the model of insulin resistance. It is investigated that ASMase activation results in insulin resistance through non-inflammatory signal HMGB1 (high mobility group box 1) of NLRP3 inflammasome. Next, 2 type diabetic mice and patients are used to detect the role of ASMase/NLRP3 inflammasome signal pathway in endothelial injury and vascular dysfunction. Lastly, based on the ASMase/NLRP3 inflammasome signal pathway, it is tested that argirein, natural product extracted from rheum officinale, alleviates vascular lesion in 2 type diabetes. Our study reveals new mechanisms of vascular lesion induced by insulin resistance, which provides new target of drug action to prevent and treat vascular lesion induced by early 2 type diabetes.