NLRP3炎性小体在高血压的血管平滑肌细胞表型转化与血管重构中的机制与干预靶点

Phenotypic switch of vascular smooth muscle cells (VSMCs) and vascular remodeling play a vital role in the pathogenesis and development of hypertension. The related mechanism is a key problem that calls for immediate solution. We have found that NLRP3 inflammasome and inflammatory cytokines are increased in the media of artery in spontaneously hypertensive rats. Preliminary studies in our lab have shown that shRNA interference targeting NLRP3 reverses the phenotypic switch, proliferation and migration of primary VSMCs from hypertensive rats. These results suggest that NLRP3 inflammasome plays a key role in the VSMCs’ phenotypic switch and vascular remodeling in hypertension. Based on the crucial finding, this project is designed to investigate the role and mechanism of NLRP3 inflammasome in the VSMCs’ phenotypic switch and vascular remodeling including the proliferation, hypertrophy, migration and fibrosis of VSMCs in hypertension, and to investigate the abnormal regulation and modulation of NLRP3 inflammasome in hypertension. We focus on revealing the NLRP3 inflammasome-related key targets for preventing VSMCs’ phenotypic switch and vascular remodeling in hypertension, and especially investigating the therapeutic effects of the intervention of these targets. The significance of this project is to clarify the role, mechanisms and molecular targets of NLRP3 inflammasome in VSMCs’ phenotypic switch and vascular remodeling in hypertension. It is hopeful to provide a novel approach and an experimental foundation for treating hypertension.

血管平滑肌细胞（VSMCs）的表型转化与血管重构在高血压发生发展中起重要作用，其发生机制是迫切需要解决的关键问题。我们发现高血压大鼠动脉中膜的炎性小体和炎性因子增多，预实验显示干涉高血压大鼠原代VSMCs的NLRP3表达可逆转其表型转化、增殖和迁移，提示炎性小体在高血压的VSMCs表型转化和血管重构中起关键作用。根据这一重要发现，本项目在整体、离体血管、细胞分子和基因水平，探讨NLRP3炎性小体在高血压VSMCs表型转化和血管重构（包括增殖肥大、迁移和纤维化）中的作用与机制，探讨其调控异常在VSMCs表型转化和血管重构中的作用与分子机制，特别是发现NLRP3炎性小体及其上下游信号分子的关键靶点，研究干预这些关键靶点对VSMCs表型转化、血管重构和高血压的防治作用，有望阐明NLRP3炎性小体在高血压VSMCs表型转化和血管重构中的作用、分子机制与干预靶点，为防治高血压提供新思路和方法。

血管平滑肌细胞（VSMCs）的表型转化与血管重构在高血压发生发展中起重要作用，血管的慢性炎症是引起VSMCs的表型转化与血管重构的关键因素，其发生机制是迫切需要解决的关键问题。本项目探讨了NLRP3炎性小体在高血压的VSMCs表型转化与血管重构中的重要作用、机制与干预靶点。我们发现自发性高血压大鼠（SHR）主动脉中膜NLRP3炎性小体激活和表型转换，沉默NLRP3阻止SHR的VSMCs炎性小体激活和表型转换、增生、迁移和肥大，NFκB激活可促进NLRP3炎性小体的激活和VSMCs表型转换，而组蛋白乙酰化是引起NFκB激活和随后的NLRP3炎性小体激活的重要机制，抑制组蛋白乙酰化减轻高血压和血管重构。NLRP3炎性小体激活在Ang II引起的VSMCs表型转换、增殖、高血压和血管重构中起重要作用。BCL6负性调控肾脏的NLRP3转录、减轻SHR的高血压和炎性小体激活和炎症。FNDC5通过抑制NFκB介导的NLRP3炎性小体激活，抑制oxLDL诱导的VSMC泡沫细胞形成和单核细胞粘附，抑制SHR血管外膜成纤维细胞（AFs）和VSMCs的表型转换、增殖、迁移和氧化应激。FNDC5基因敲除可加重肥胖引起的胰岛素抵抗、脂肪组织炎症、AMPK抑制、巨噬细胞募集和极化，FNDC5过表达降低SHR的血压和减轻血管重构。姜黄素抑制NLRP3炎性小体激活，减轻高血压和血管重构。本项目揭示了VSMCs的NLRP3炎性小体激活在高血压等血管病发病机制中的重要作用及其分子机制，阻止NLRP3炎性小体激活可抑制VSMCs表型转换、增殖和迁移，并减轻高血压和血管重构。组蛋白乙酰化引起的NFκB激活是导致NLRP3炎性小体激活的重要机制。FNDC5、姜黄素和BCL6能抑制NLRP3炎性小体激活，进而减轻高血压和血管重构，干预这些靶点对能有效减轻血管炎症，进而减轻高血压等炎症性血管病，不仅具有重要的理论意义，而且为防治高血压等血管病提供新策略。