Fibroblast growth factor 21 inhibited ischemic arrhythmias via targeting miR-143/EGR1 axis
Fibroblast growth factor 21 inhibited ischemic arrhythmias via targeting miR-143/EGR1 axis
复制标题
成纤维细胞生长因子 21 通过靶向 miR-143/EGR1 轴抑制缺血性心律失常。
DOI：
10.1007/s00395-019-0768-4
复制
发表时间：
2020-01-04
影响因子：
9.5
通讯作者：
Yang, Baofeng
中科院分区：
文献类型：
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作者：
Li, Jiamin;Xu, Chaoqian;Yang, Baofeng
室性心律失常是心肌梗死（MI）患者心源性猝死的最常见原因。成纤维细胞生长因子21（FGF 21）已被证明在心血管和代谢性疾病中发挥重要作用。然而，FGF 21对MI后室性心律失常的影响尚未得到解决。本研究旨在探讨FGF 21对心肌梗死后室性心律失常的药理作用。成年雄性小鼠给予或不给予重组人碱性成纤维细胞生长因子21（rhbFGF 21），通过程序电刺激和光学标测技术评估心律失常的易感性。在这里，我们发现rhbFGF 21给药减少了室性心动过速（VT）的发生，改善了心外膜传导速度，缩短了梗死小鼠心脏90%时的动作电位时程（APD 90）。FGF 21可改善心肌电生理重构，其机制表现为心肌梗死边缘区的I Na和I K 1电流密度降低。体外实验也证实，FGF 21可以改善氧化应激诱导的心室肌细胞I Na和I K 1电流的功能障碍。我们进一步发现，氧化应激诱导的早期生长反应蛋白1（EGR 1）表达下调导致梗死后心肌中INa和IK 1的减少，FGF 21可能将EGR 1募集到SCN 5A和KCNJ 2启动子区，在转录水平上调NaV1.5和Kir2.1的表达。此外，miR-143被鉴定为EGFR 1的上游，并介导心肌细胞中FGF 21诱导的EGFR 1上调。总的来说，rhbFGF 21通过调节miR-143-EGR 1-NaV1.5/Kir2.1轴有效地抑制了梗死后心脏的室性心律失常，这为临床缺血性心律失常提供了新的治疗策略。
Ventricular arrhythmia is the most common cause of sudden cardiac death in patients with myocardial infarction (MI). Fibroblast growth factor 21 (FGF21) has been shown to play an important role in cardiovascular and metabolic diseases. However, the effects of FGF21 on ventricular arrhythmias following MI have not been addressed yet. The present study was conducted to investigate the pharmacological action of FGF21 on ventricular arrhythmias after MI. Adult male mice were administrated with or without recombinant human basic FGF21 (rhbFGF21), and the susceptibility to arrhythmias was assessed by programmed electrical stimulation and optical mapping techniques. Here, we found that rhbFGF21 administration reduced the occurrence of ventricular tachycardia (VT), improved epicardial conduction velocity and shorted action potential duration at 90% (APD90) in infarcted mouse hearts. Mechanistically, FGF21 may improve cardiac electrophysiological remodeling as characterized by the decrease ofINaandIK1current density in border zone of infarcted mouse hearts. Consistently, in vitro study also demonstrated that FGF21 may rescue oxidant stress-induced dysfunction ofINaandIK1currents in cultured ventricular myocytes. We further found that oxidant stress-induced down-regulation of early growth response protein 1 (EGR1) contributed toINaandIK1reduction in post-infarcted hearts, and FGF21 may recruit EGR1 into theSCN5AandKCNJ2promoter regions to up-regulate NaV1.5 and Kir2.1 expression at transcriptional level. Moreover, miR-143 was identified as upstream of EGR1 and mediated FGF21-induced EGR1 up-regulation in cardiomyocytes. Collectively, rhbFGF21 administration effectively suppressed ventricular arrhythmias in post-infarcted hearts by regulating miR-143-EGR1-NaV1.5/Kir2.1 axis, which provides novel therapeutic strategies for ischemic arrhythmias in clinics.