Fibroblast Growth Factor 21 Protects Against Atrial Remodeling via Reducing Oxidative Stress

Miao Chen; Jiawei Zhong; Zhen Wang; Hongfei Xu; Heng Chen; Xingang Sun; Yunlong Lu; Lu Chen; Xudong Xie; Liangrong Zheng

doi:10.3389/fcvm.2021.720581

Fibroblast Growth Factor 21 Protects Against Atrial Remodeling via Reducing Oxidative Stress

Front Cardiovasc Med. 2021 Oct 11:8:720581. doi: 10.3389/fcvm.2021.720581. eCollection 2021.

Authors

Miao Chen¹, Jiawei Zhong¹, Zhen Wang¹, Hongfei Xu², Heng Chen¹, Xingang Sun¹, Yunlong Lu¹, Lu Chen¹, Xudong Xie¹, Liangrong Zheng¹

Affiliations

¹ Department of Cardiology and Atrial Fibrillation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Department of Cardiovascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Abstract

Aim: The structural and electrical changes in the atrium, also known as atrial remodeling, are the main characteristics of atrial fibrillation (AF). Fibroblast growth factor 21 (Fgf21) is an important endocrine factor, which has been shown to play an important role in cardiovascular diseases. However, the effects of Fgf21 on atrial remodeling have not been addressed yet. The purpose of the present study is to evaluate the effects of Fgf21 on atrial remodeling. Methods and Results: Adult mice were treated with Ang II, and randomly administrated with or without Fgf21 for 2 weeks. The susceptibility to AF was assessed by electrical stimulation and optical mapping techniques. Here, we found that Fgf21 administration attenuated the inducibility of atrial fibrillation/atrial tachycardia (AF/AT), improved epicardial conduction velocity in the mice atria. Mechanistically, Fgf21 protected against atrial fibrosis and reduced oxidative stress of the atria. Consistently, in vitro study also demonstrated that Fgf21 blocked the upregulation of collagen by Tgf-β in fibroblasts and attenuated tachypacing-induced oxidative stress including reactive oxygen species (ROS), Tgf-β, and ox-CaMKII in atrial myocytes. We further found that Fgf21 attenuated oxidative stress by inducing antioxidant genes, such as SOD2 and UCP3. Fgf21 also improved tachypacing-induced myofibril degradation, downregulation of L-type calcium channel, and upregulation of p-RyR2, which implicated protective effects of Fgf21 on structural and electrical remodeling in the atria. Moreover, Nrf2 was identified as a downstream of Fgf21 and partly mediated Fgf21-induced antioxidant gene expression in atrial myocytes. Conclusion: Fgf21 administration effectively suppressed atrial remodeling by reducing oxidative stress, which provides a novel therapeutic insight for AF.

Keywords: atrial fibrillation; atrial remodeling; fibroblast growth factor 21; nuclear factor erythroid 2-related factor 2; oxidative stress.