AT1R介导的巨噬细胞功能失常在盐敏感性高血压血管胰岛素抵抗中的作用机制研究

血管胰岛素PI3K/NO信号通路在维持代谢和心血管内环境功能稳定中有重要作用。临床上高血压和代谢性疾病常相互共生, 血管胰岛素抵抗可能是维系二者共生的纽带或病理基础，其机制不清。 我们前期结果显示盐敏感性高血压鼠腹腔巨噬细胞血管紧张素一型受体（AT1R）和M1炎性因子呈高表达，阻断AT1R减少血管巨噬细胞浸润和M1炎性因子表达，改善胰岛素舒血管功能。据此，我们提出假说：在盐敏感性高血压髓系AT1R高表达引起单核巨噬细胞功能失常，血管壁浸润，释放TNFa抑制血管胰岛素PI3K/NO信号通路并引起血管损伤。本项目拟通过髓系细胞条件性AT1R基因敲处鼠和TNFa基因敲处鼠，流式细胞组织分选，单核细胞迁移同位素示踪技术，骨髓移植以及近代分子生物学技术等多种实验手段验证上述假说。本项目在阐明高血压和血管胰岛素抵抗免疫损伤机制，探索新的免疫靶分子（AT1R/TNFa）治疗高血压和代谢性疾病有重要意义。

The vascular insulin PI3K/NO signaling pathway plays an important role in maintenance of metabolic and vascular homeostasis. Clinically, hypertension is always associated with metabolic diseases, and Insulin resistance may be the link and pathological basis for maintaining the symbiotic relationship between the two. However,the underlying mechanism is still unclear. We have previously shown that AT1R was highly expressed in the peritoneal macrophages of salt-sensitive hypertensive Dahl rats, the blockade of AT1R improved insulin-mediated vascular relaxation associated with reduced the infiltration of monocytes/macrophages in the vascular wall. Therefore, we propose that upregulation of myeloid AT1R induces monocyte/macrophage dysfunction and recruitments in the vascular wall, which release tumor nuclear factor (TNFa) which inhibits insulin PI3K/NO pathway, resulting in vascular insulin resistance and vascular injury. We will use conditional myeloid AT1R knockout and TNFa knockout mice, flow cytometry cell sorting analysis, in vivo trace of isotope-labeled monocyte migration of vascular wall，bone marrow transportation and other cut-edge molecular biology techniques to test the hypothesis. The proposed studies will help us to understand the immune mechanisms of hypertension and vascular insulin resistance, and may identify AT1R/TNFa as new target molecules for immunotherapy of hypertensive and metabolic diseases.