Fibroblast growth factor 21 inhibited ischemic arrhythmias via targeting miR-143/EGR1 axis

内科学 室性心动过速 心脏病学 医学 FGF21型 心肌梗塞 心室重构 内分泌学 成纤维细胞生长因子 受体
作者
Jiamin Li,Chaoqian Xu,Yining Liu,Yuanshi Li,Sijia Du,Ruijie Zhang,Yuehang Sun,Ronghao Zhang,Ying Wáng,Hongru Xue,Sha Ni,Mavlikhanova Asiya,Genlong Xue,Yanyao Li,Ling Shi,Desheng Li,Zhenwei Pan,Yong Zhang,Zhiguo Wang,Benzhi Cai,Ning Wang,Baofeng Yang
出处
期刊:Basic Research in Cardiology [Springer Nature]
卷期号:115 (2) 被引量:44
标识
DOI:10.1007/s00395-019-0768-4
摘要

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 of INa and IK1 current density in border zone of infarcted mouse hearts. Consistently, in vitro study also demonstrated that FGF21 may rescue oxidant stress-induced dysfunction of INa and IK1 currents in cultured ventricular myocytes. We further found that oxidant stress-induced down-regulation of early growth response protein 1 (EGR1) contributed to INa and IK1 reduction in post-infarcted hearts, and FGF21 may recruit EGR1 into the SCN5A and KCNJ2 promoter 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.
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