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

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Abstract

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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Abbreviations

AMI:

Acute myocardial infarction

APD:

Action potential duration

CMI:

Chronic myocardial infarction

CV:

Conduction velocity

EGR1:

Early growth response protein 1

ES:

Electrical stimulation

FGF:

Fibroblast growth factor

ip:

Intraperitoneal injection

LAD:

Left anterior-descending

LV:

Left ventricle

MI:

Myocardial infarction

NC:

Negative control

NS:

Normal saline

PVCs:

Premature ventricular complexes

rhbFGF21:

Recombinant human basic FGF21

Spon:

Spontaneity

VEB:

Ventricular ectopic beats

VF:

Ventricular fibrillation

VT:

Ventricular tachycardia

WT:

Wild-type

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Acknowledgements

We thank Xiaokun Li and Chi Zhang from Wenzhou Medical University (Wenzhou, China) for providing rhbFGF21 in this study.

Funding

The work was supported by Heilongjiang Touyan Innovation Team Program [BFY, CQX, NW, BZC, YZ, ZWP]; the National Key R&D Program of China [2017YFC1307403 to BFY]; and the National Nature Science Foundation of China [Grant No. 81730012 to BFY, 81670207 to CQX, 81573425 and 81773733 to NW]; Natural Science Foundation of Heilongjiang Province [H2016010 to NW]; Foundation of Heilongjiang postdoctoral [LBH-Z18166 to JML]; Basic scientific research Foundation of universities in heilongjiang province [31041180028 to JML] and Outstanding Youth Fostering Foundation of Vihan Academician [NW].

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  1. Jiamin Li and Chaoqian Xu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China

    Jiamin Li, Yining Liu, Sijia Du, Ruijie Zhang, Yuehang Sun, Ronghao Zhang, Ying Wang, 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

  2. Mudanjiang Medical University, Mudanjiang, 157000, China

    Chaoqian Xu

  3. Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, China

    Yuanshi Li

  4. Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, 150086, China

    Yong Zhang

  5. Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University (Institute of Clinical Pharmacy, The University Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions), Harbin, 150081, China

    Benzhi Cai

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  1. Jiamin Li
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Contributions

BY, NW and BC designed the experiments, performed the experiments, wrote the manuscript. JL and CX helped perform the experiments and edited the manuscript. YL, RuZ, RoZ, YW, MA performed molecular biology, and edited the manuscript. YL participated in statistical analysis. HX and SN cultured the cells, and edited the manuscript. SD, YL, YS performed whole-cell patch-clamp. GX, LS and DL performed optical mapping. ZW, ZP and YZ helped design the experiments, and edited the manuscript.

Corresponding authors

Correspondence to Benzhi Cai, Ning Wang or Baofeng Yang.

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The authors declare that they have no competing interest.

Additional information

The corresponding authors have the following order: 1st corresponding author: Baofeng Yang, 2nd corresponding author: Ning Wang, 3rd corresponding author: Benzhi Cai.

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Li, J., Xu, C., Liu, Y. et al. Fibroblast growth factor 21 inhibited ischemic arrhythmias via targeting miR-143/EGR1 axis. Basic Res Cardiol 115, 9 (2020). https://doi.org/10.1007/s00395-019-0768-4

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