Key result
AAV9-CYP2J2 gene delivery cuts AF inducibility by an absolute ~50% in pressure-overload mice.
Why the study?
Despite established cardiovascular protective effects of CYP2J2/EET, whether CYP2J2/EET has a preventive effect on atrial fibrillation remained to be determined.
Does AAV9-CYP2J2 gene delivery reduce atrial fibrillation inducibility and structural remodeling in a mouse model of chronic pressure overload?
Does AAV9-CYP2J2 gene delivery reduce atrial fibrillation inducibility and structural remodeling in a mouse model of chronic pressure overload?
CYP2J2/EET overexpression reduces atrial fibrillation vulnerability and fibrosis in a chronic pressure overload mouse model, highlighting a potential upstream therapeutic pathway.
No immediate clinical implications for AF; leaves open CYP2J2/EET as upstream target in human pressure-overload models.
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.
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Li et al. (2019) studied Atrial fibrillation (mouse model of chronic pressure overload) (n=64). AAV9-CYP2J2 vs. AAV9-GFP or abdominal aortic constriction alone was evaluated on Atrial fibrillation inducibility (p=<0.05). AAV9-CYP2J2 gene delivery reduced atrial fibrillation inducibility to 30% compared to 80% in untreated abdominal aortic constriction mice.
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