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.

Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes

“…It is well recognized that interindividual variations in drug response, including a lack of efficacy and adverse drug reactions represent the major challenges for personalized medicine. Although a drug effect is complex and depends on many factors, some human gene polymorphisms already have been associated with substantial differences in the metabolism or effects of drugs [28], and some are now being used to predict toxic metabolite-related disease or a clinical response [29][30][31][32][33][34][35]_ENREF_1. _ENREF_1However, as the principal electron donor for the drug metabolizing CYPs, little is known about the effect of POR gene polymorphisms on the activities of CYPs with different genotypes.…”

ZDHXB-101 (3′,5-Diallyl-2, 4′-dihydroxy-[1,1′-biphen-yl]-3,5′-dicarbaldehyde) protects against airway remodeling and hyperresponsiveness via inhibiting both the activation of the mitogen-activated protein kinase and the signal transducer and activator of transcription-3 signaling pathways

“…Inhibitors of sEH increased the EETs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma [23]. In experimental studies, inhibitors of sEH have been shown to reduce lung injury caused by lipopolysaccharide [24,25], pulmonary fibrosis induced by bleomycin [15], asthma caused by OVA [12], and airway inflammation induced by cigarette smoke [26,27]. EETs can relax human airway smooth muscles and directly activate reconstituted KCa channels [28] and are potent modulators of the hyperreactivity triggered by TNF-α in human airway smooth muscle cells [29].…”

“…It has been previously shown that 14,15-EETs have important biological effects including anti-inflammation and anti-remodeling. Therefore, in our study we chose to study the anti-inflammation and anti-remodeling effects of 14,15-EETs [11,12]. All EETs, including 14,15-EETs, are metabolized to the less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH) [13].…”

Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Chronic Ethanol‐Induced Cardiac Fibrosis by Restoring Autophagic Flux

“…Cardiac EET levels were analyzed using liquid chromatograph/mass spectrometer (LC/MS) as described previously (Zhou et al., ).…”

“…Transwell cell culture chambers (Corning, Cambridge, MA) with 8.0‐ μ m pore size polycarbonate membranes were used to evaluate cell migration ability in vitro as described before (Zhou et al., ).…”