内皮盐皮质激素受体与自噬介导肥胖相关性高血压血管损害的机制研究

血管损害是高血压和肥胖患者常见靶器官损害，是心血管疾病死亡的重要原因。明确肥胖相关性高血压血管损害的机制至关重要。新近研究发现内皮盐皮质激素受体（mineralocorticoid receptor，MR）激活介导肥胖相关的血管损害，但其机制尚不明确。本课题组前期研究发现MR阻滞剂可以改善肥胖相关性高血压患者血管舒张功能，在高血压动物模型主动脉内皮MR表达升高，主动脉内皮细胞损伤可导致自噬水平降低，但血管内皮MR及自噬对肥胖相关性高血压血管损害机制不明确。因此，本研究以实验性肥胖性相关性高血压小鼠和内皮特异MR敲除的肥胖性相关性高血压小鼠为研究对象，探讨MR及自噬与肥胖相关性高血压血管损害的关系及其是否存在性别差异，并进一步探讨MR调控自噬介导肥胖相关性高血压血管损害的机制以及MR调控自噬的信号通路。本研究结果对于揭示MR在肥胖相关性高血压血管损害的机制，识别其药物干预的靶点具有重要意义。

Vascular damage is a common target organ damage in patients with hypertension and obesity, which is also an important cause of cardiovascular disease morbidity and mortality. It is very important to clarify the mechanism of vascular damage in obesity-related hypertension. Recent studies have found that endothelial mineralocorticoid receptor (MR) activation mediates obesity-related vascular damage, but the mechanism is not clear. Our previous study found that MR blockers could improve the vasodilation function of obesity-related hypertension patients. In hypertensive animal model, the expression of MR in aortic endothelium increased, and the injury of aortic endothelial cells could lead to the decrease of autophagy. However, the mechanism of vascular endothelial MR and autophagy on vascular damage in obesity-related hypertension is not clear. In this study, experimental obesity-related hypertensive mice and endothelial-specific MR knock-out obesity-related hypertensive mice were used to investigate the relationship between vascular endothelial MR, autophagy and obesity-related hypertensive vascular damage and whether there are gender differences. Further study to explore the mechanism of MR regulation of autophagy involved in obesity-related hypertension vascular damage and the signal pathway of MR regulation of autophagy by using drug-targeted intervention of MR and endothelial specific knock-out MR. Exploration of the mechanisms of in vascular damage in obesity-related hypertension may help to identify the targets of drug intervention.