TNFa及其下游分子miR-155在盐敏感性高血压及其相关血管内皮细胞功能障碍中的作用研究

血管内皮细胞功能障碍与高血压及其血管并发症密切相关，修复受损的内皮细胞功能是目前研究的热点。我们前期结果显示在盐敏感性高血压中血管内皮细胞功能障碍与血管紧张素ⅡI型受体（AT1R）/NFkB炎性通路的激活及内皮细胞eNOS/NO降低有关,在培养的血管内皮细胞中炎性细胞因子TNFa增加miR-155并抑制eNOS，提示TNFa在诱导内皮细胞功能损害中的作用。本研究拟在前期工作基础上，利用多种基因缺乏鼠，骨髓移植、基因转染和内皮细胞功能检测等方法，深入探讨TNFa/miR-155在盐敏感性高血压及相关内皮细胞功能障碍中的作用和机制，论证TNFa/miR-155是激活AT1R/NFkB信号通路的下游分子引起高血压，eNOS/NO抑制，血管内皮细胞功能障碍和靶器官损害的关键信号分子这一假说。由此探索修复内皮细胞障碍的靶分子，为开发以TNFa关联分子为靶标修复血管内皮细胞的抗高血压治疗尊定理论基础。

Vascular endothelial dysfunction is closely associated with hypertension and vascular complications. How to repair damaged endothelial function is a hot topic in the field of cardiovascular and hypertensive diseases. We have previously shown that endothelial dysfunction in salt-sensitive hypertension was linked to upregulation of angiotensin II type I receptor (AT1R)/NFkB as well as decreased eNOS/NO signaling pathway, preinflammatory moelcule TNFa increased endothelial miR-155 expression and inhibited eNOS in endothelian cells, suggesting an important role of TNFa in induction of endothelial dysfunction. As a continuation of our previous studies, we propose to use a set of combinatory methods including knockout mice, bone marrow transplantation, gene transfection as well as evaluation of endothelial function to determine the molecular mechanisms of TNFa?and miR-155 in the induction of endothelial dysfunction associated with salt-sensitive hypertension. The proposed studies will identify TNFa/ miR-155 as downstream molecules of NFkB activation that induce endothelial dysfunction in salt-sensitive hypertension, and provide important scientific evidences for the development of new antihypetenvie therapy to target TNFa and its related molecules with the improvement of endothelial function.