Zhou Chi, Huang Jin, Chen Junxiong, Lai Jinsheng, Zhu Fasheng, Xu Xizhen, Wang Dao Wen
Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Cell Physiol Biochem. 2016;39(2):721-39. doi: 10.1159/000445663. Epub 2016 Jul 27.
Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids (AA) to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the treatment of cardiovascular diseases, but little is known about its role on adventitial remodeling.
We used C57BL/6J mice in vivo and primary rat adventitial fibroblasts (AFs) in vitro treated with Angiotensin II to investigate the effects of CYP2J2 gene delivery and exogenous EETs administration on adventitial remodeling.
CYP/sEH system was found to exist in human adventitia, and involved in adventitial remodeling process. Exogenous EETs administration significantly inhibited Ang II-induced AFs activation, characterized by differentiation, proliferation, migration, and collagen synthesis. These protective effects were partially reversed by PPARx03B3; antagonist GW9662 pretreatment or SOCS3 siRNA transfection. EETs suppressed Ang II-induced Ix03BA;Bα phosphorylation, subsequent NF-x03BA;B nuclear translocation via PPARx03B3; dependent signaling pathway in AFs. Additionally, EETs reduced Ang II-induced JAK2, STAT3 phosphorylation and subsequent phosphor-STAT3 nuclear translocation, which were mediated by SOCS3 induction but independent of PPARx03B3; activation. Furthermore, rAAV-CYP2J2 gene delivery reduced vessel wall thickening, AFs differentiation, proliferation and collagen deposition in aortic adventitia induced by Ang II infusion, which were mediated by NF-x03BA;B and SOCS3/JAK/STAT signaling pathways in blood pressure dependent and independent manner, respectively.
We concluded that CYP2J2 overexpression attenuated Ang II-induced adventitial remodeling via PPARx03B3;-dependent NF-x03BA;B and PPARx03B3;-independent SOCS3/JAK/STAT inflammatory signaling pathways.
细胞色素P450（CYP）环氧化酶将花生四烯酸（AA）代谢生成环氧二十碳三烯酸（EETs），其在心血管疾病治疗中发挥有益作用，但对其在外膜重塑中的作用知之甚少。
我们在体内使用C57BL/6J小鼠，在体外使用经血管紧张素II处理的原代大鼠外膜成纤维细胞（AFs），以研究CYP2J2基因递送和外源性EETs给药对外膜重塑的影响。
发现CYP/sEH系统存在于人类外膜中，并参与外膜重塑过程。外源性EETs给药显著抑制血管紧张素II诱导的AFs激活，其特征为分化、增殖、迁移和胶原蛋白合成。PPARγ拮抗剂GW9662预处理或SOCS3 siRNA转染可部分逆转这些保护作用。EETs通过AFs中依赖PPARγ的信号通路抑制血管紧张素II诱导的IκBα磷酸化及随后的NF-κB核转位。此外，EETs减少血管紧张素II诱导的JAK2、STAT3磷酸化及随后的磷酸化STAT3核转位，这是由SOCS3诱导介导但独立于PPARγ激活。此外，rAAV-CYP2J2基因递送减少了血管紧张素II输注诱导的主动脉外膜血管壁增厚、AFs分化、增殖和胶原蛋白沉积，分别由依赖血压和独立于血压的NF-κB和SOCS3/JAK/STAT信号通路介导。
我们得出结论，CYP2J2过表达通过依赖PPARγ的NF-κB和不依赖PPARγ的SOCS3/JAK/STAT炎症信号通路减弱血管紧张素II诱导的外膜重塑。
