title: 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhou
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Junxiong
authors.initials: J
authors.lastname: Chen
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Lai
authors.forename: Fasheng
authors.initials: F
authors.lastname: Zhu
authors.forename: Xizhen
authors.initials: X
authors.lastname: Xu
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism* / Q000494:pharmacology; D063194:Adventitia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: C000717350:CYP2J2 protein, human; D018836:Inflammation Mediators; D000071223:Suppressor of Cytokine Signaling 3 Protein; D000804:Angiotensin II; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid