Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Cell Mol Med. 2020 Jan;24(1):862-874. doi: 10.1111/jcmm.14796. Epub 2019 Nov 20.
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.
越来越多的证据充分证实 CYP2J2/EET 对心血管系统具有保护作用。本研究旨在确定 CYP2J2/EET 是否对心房颤动 (AF) 具有预防作用，并探讨其潜在机制。野生型小鼠在腹主动脉缩窄 (AAC) 手术前注射 AAV9-CYP2J2 或不注射。8 周后，与野生型小鼠相比，AAC 小鼠的 AF 易感性更高，AF 持续时间更长，而 AAV9-CYP2J2 则显著减弱。此外，AAV9-CYP2J2 减少了 AAC 小鼠的心房纤维化面积和胶原-I/III 的沉积，同时阻断了 TGF-β/Smad-2/3 信号通路，并恢复了 Smad-7 的表达。在体外，分离的心房成纤维细胞给予 TGF-β1、EET、EEZE、GW9662、Smad-7 siRNA 和前体 miR-21，结果表明 EET 主要通过 Smad-7 抑制 miR-21 来抑制心房成纤维细胞的分化。此外，AAC 手术引起的炎症细胞因子增加和 NF-κB 通路激活也被 AAV9-CYP2J2 治疗显著减弱。这些 CYP2J2/EET 的作用部分被 PPAR-γ 拮抗剂 GW9662 阻断。综上所述，本研究表明，CYP2J2/EET 通过抑制 MiR-21 对 Smad-7 的作用来改善心房纤维化，通过抑制 NF-κB 通路来减轻心房炎症反应，从而降低 AF 的易感性，CYP2J2/EET 的作用至少部分通过 PPAR-γ 激活来实现。我们的发现为 AF 提供了一种新的上游治疗策略。
