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Published on: June 29, 2022
CYP2J2/EET reduces vulnerability to atrial fibrillation in chronic pressure overload mice
Xuguang Li1, Feng Zhu1, Weidong Meng1
1Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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.
Insights
The enzyme CYP2J2/EET protects the cardiovascular system by preventing atrial fibrillation (AF). It reduces atrial fibrosis and inflammation via specific molecular pathways, offering a potential new therapeutic strategy for AF.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Growing evidence supports the cardioprotective role of CYP2J2/EET.
- Atrial fibrillation (AF) is a significant cardiovascular condition with complex underlying mechanisms.
Purpose of the Study:
- To investigate the preventive effect of CYP2J2/EET on AF.
- To elucidate the molecular mechanisms by which CYP2J2/EET exerts its effects on AF.
Main Methods:
- AAV9-CYP2J2 was administered to wild-type mice undergoing abdominal aortic constriction (AAC).
- AF inducibility, duration, atrial fibrosis, collagen deposition, and signaling pathways (TGF-β/Smad, NF-κB) were assessed.
- In vitro studies utilized isolated atrial fibroblasts treated with TGF-β1, EET, and other modulators.
Main Results:
- AAV9-CYP2J2 treatment significantly attenuated AF inducibility and duration in AAC mice.
- CYP2J2/EET reduced atrial fibrosis and collagen deposition by modulating TGF-β/Smad signaling and upregulating Smad-7.
- EET inhibited miR-21, thereby restraining atrial fibroblast differentiation.
- AAV9-CYP2J2 treatment blunted inflammatory cytokines and NF-κB pathway activation.
- Effects were partially mediated through PPAR-γ activation.
Conclusions:
- CYP2J2/EET ameliorates atrial fibrosis and reduces AF vulnerability.
- Mechanisms involve modulating fibroblast activation via Smad-7/miR-21 and suppressing inflammation through NF-κB pathways.
- CYP2J2/EET acts, at least partly, via PPAR-γ activation, presenting a novel therapeutic strategy for AF.
