NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension.
NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension.
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NLRP3 炎性体激活有助于高血压中 VSMC 表型转化和增殖。
DOI：
10.1038/cddis.2017.470
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发表时间：
2017-10-05
影响因子：
9
通讯作者：
Zhu GQ
中科院分区：
文献类型：
--
作者：
Sun HJ;Ren XS;Xiong XQ;Chen YZ;Zhao MX;Wang JJ;Zhou YB;Han Y;Chen Q;Li YH;Kang YM;Zhu GQ
炎症参与高血压的发病机制。 NLRP3 炎症小体激活是通过 caspase-1 激活产生炎症反应的强大介质。本研究旨在确定 NLRP3 炎症小体在高血压血管平滑肌细胞 (VSMC) 表型调节和增殖中的作用和机制。实验在自发性高血压大鼠（SHR）和原发性主动脉 VSMC 中进行。在 SHR 的主动脉中层和 SHR 的 VSMC 中观察到 NLRP3 炎性体激活。 NLRP3 的敲低抑制了 SHR 衍生的 VSMC 中的炎性体激活、VSMC 表型转化和增殖。在 SHR 衍生的 VSMC 和 SHR 的主动脉中层中观察到 NFκB 激活、组蛋白乙酰化和组蛋白乙酰转移酶表达增加。染色质免疫沉淀分析显示，体内和体外 NLRP3 启动子处的组蛋白乙酰化、p65-NFκB 和 Pol II 占据增加。用 BAY11-7082 抑制 NFκB 或用姜黄素抑制组蛋白乙酰转移酶可阻止 NLRP3 炎性体激活、VSMC 表型转换和 SHR 中 VSMC 的增殖。此外，姜黄素抑制 NFκB 激活。 NLRP3 基因沉默可改善 SHR 主动脉的高血压、血管重塑、NLRP3 炎性体激活和表型转换。这些结果表明，NLRP3 炎症小体对组蛋白乙酰化和 NFκB 激活的激活反应有助于高血压中 VSMC 表型转换、增殖和血管重塑。
Inflammation is involved in pathogenesis of hypertension. NLRP3 inflammasome activation is a powerful mediator of inflammatory response via caspase-1 activation. The present study was designed to determine the roles and mechanisms of NLRP3 inflammasome in phenotypic modulation and proliferation of vascular smooth muscle cells (VSMCs) in hypertension. Experiments were conducted in spontaneously hypertensive rats (SHR) and primary aortic VSMCs. NLRP3 inflammasome activation was observed in the media of aorta in SHR and in the VSMCs from SHR. Knockdown of NLRP3 inhibited inflammasome activation, VSMC phenotypic transformation and proliferation in SHR-derived VSMCs. Increased NFκB activation, histone acetylation and histone acetyltransferase expression were observed in SHR-derived VSMCs and in media of aorta in SHR. Chromatin immunoprecipitation analysis revealed the increased histone acetylation, p65-NFκB and Pol II occupancy at the NLRP3 promoter in vivo and in vitro. Inhibition of NFκB with BAY11-7082 or inhibition of histone acetyltransferase with curcumin prevented the NLRP3 inflammasome activation, VSMC phenotype switching and proliferation in VSMCs from SHR. Moreover, curcumin repressed NFκB activation. Silencing of NLRP3 gene ameliorated hypertension, vascular remodeling, NLRP3 inflammasome activation and phenotype switching in the aorta of SHR. These results indicate that NLRP3 inflammasome activation response to histone acetylation and NFκB activation contributes to VSMC phenotype switching and proliferation and vascular remodeling in hypertension.
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影响因子：
4.6
作者：
Chiba T;Itoh T;Tabuchi M;Nakazawa T;Satou T
通讯作者：
Satou T
影响因子：
4.6
作者：
Chen X;Shi X;Zhang X;Lei H;Long S;Su H;Pei Z;Huang R
通讯作者：
Huang R
影响因子：
5.5
作者：
Chiong M;Cartes-Saavedra B;Norambuena-Soto I;Mondaca-Ruff D;Morales PE;García-Miguel M;Mellado R
通讯作者：
Mellado R
影响因子：
8.7
作者：
Elliott EI;Sutterwala FS
通讯作者：
Sutterwala FS
影响因子：
4.6
作者：
Bao MH;Li JM;Luo HQ;Tang L;Lv QL;Li GY;Zhou HH
通讯作者：
Zhou HH