CYP2J2-Derived EETs Attenuated Angiotensin II-Induced Adventitial Remodeling via Reduced Inflammatory Response

Abstract

Background: 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. Methods: 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. Results: 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 PPARγ antagonist GW9662 pretreatment or SOCS3 siRNA transfection. EETs suppressed Ang II-induced IκBα phosphorylation, subsequent NF-κB nuclear translocation via PPARγ 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 PPARγ 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-κB and SOCS3/JAK/STAT signaling pathways in blood pressure dependent and independent manner, respectively. Conclusion: We concluded that CYP2J2 overexpression attenuated Ang II-induced adventitial remodeling via PPARγ-dependent NF-κB and PPARγ-independent SOCS3/JAK/STAT inflammatory signaling pathways.