CYP2J2/EET reduces vulnerability to atrial fibrillation in chronic pressure overload mice

Abstract

Growing evidence has well established the protective effects of CYP2J2/EET on the cardiovascular system. The aim of the present study was to determine whether CYP2J2/EET has a preventive effect on atrial fibrillation (AF) and to investigate the underlying mechanisms. Wild‐type mice were injected with or without AAV9‐CYP2J2 before abdominal aortic constriction (AAC) operation. After 8 weeks, compared with wild‐type mice, AAC mice display higher AF inducibility and longer AF durations, which were remarkably attenuated with AAV9‐CYP2J2. Also, AAV9‐CYP2J2 reduced atrial fibrosis area and the deposit of collagen‐I/III in AAC mice, accompanied by the blockade of TGF‐β/Smad‐2/3 signalling pathways, as well as the recovery in Smad‐7 expression. In vitro, isolated atrial fibroblasts were administrated with TGF‐β1, EET, EEZE, GW9662, SiRNA Smad‐7 and pre‐MiR‐21, and EET was demonstrated to restrain the differentiation of atrial fibroblasts largely dependent on Smad‐7, due to the inhibition of EET on MiR‐21. In addition, increased inflammatory cytokines, as well as activated NF‐κB pathways induced by AAC surgery, were also significantly blunted by AAV9‐CYP2J2 treatment. These effects of CYP2J2/EET were partially blocked by GW9662, the antagonist of PPAR‐γ. In conclusion, this study revealed that CYP2J2/EET ameliorates atrial fibrosis through modulating atrial fibroblasts activation by disinhibition of MiR‐21 on Smad‐7, and attenuates atrial inflammatory response by repressing NF‐κB pathways, reducing the vulnerability to AF, and CYP2J2/EET exerts its role at least partially through PPAR‐γ activation. Our findings might provide a novel upstream therapeutic strategy for AF.

The Role of Epoxyeicosatrienoic Acids in Cardiac Remodeling

“…It was proven that the TGF-β/Smad pathway was involved in the process ( Li et al, 2020a ). They also found that similar effects were observed in the abdominal aortic constriction model, which is another pressure overload-induced cardiac remodeling model ( Li et al, 2020b ). Besides, Ang II-induced cardiac remodeling is always accompanied by cardiac fibrosis.…”

Endothelial CYP2J2 overexpression restores the BRB via METTL3‐mediated ANXA1 upregulation

“…Cytochrome P450 epoxygenase 2J2 (CYP2J2) is widely expressed in cardiac myocytes, vascular endothelium, the liver, and the pancreas in humans and is required for arachidonic acid metabolism. CYP2J2 converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (5,6‐EET; 8,9‐EET; 11,12‐EET; and 14,15‐EET) 27 . As reported, CYP2J2 and its lipid metabolites exert beneficial effects on diabetes, cardiovascular dysfunction, and central nervous diseases.…”

“…CYP2J2 converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (5,6-EET; 8,9-EET; 11,12-EET; and 14,15-EET). 27 As reported, CYP2J2 and its lipid metabolites exert beneficial effects on diabetes, cardiovascular dysfunction, and central nervous diseases. Yan Yang et al demonstrated that CYP2J2 overexpression attenuated age-related insulin resistance.…”

Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids

“…Supportive investigations determining the effects of EETs in vascular inflammation demonstrated intra-arterial perfusion of 11,12-EET decreased endothelial VCAM-1 expression and prevented the adhesion of mononuclear cells in mice following injection of TNF-α [ 219 ]. Moreover, the increase in EET levels associated with the cardiac specific overexpression of CYP2J2-attenuated atrial fibrosis and inflammatory responses in a mouse model of atrial fibrillation induced by constriction of the abdominal aorta [ 221 ]. Treatment with EET analogs limited myocardial fibrosis and macrophage infiltration, decelerating the progression of MI-induced HF in rats subjected to ligation of left anterior descending (LAD) coronary artery [ 192 ].…”