Chen Miao, Zhong Jiawei, Wang Zhen, Xu Hongfei, Chen Heng, Sun Xingang, Lu Yunlong, Chen Lu, Xie Xudong, Zheng Liangrong
Department of Cardiology and Atrial Fibrillation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Department of Cardiovascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Front Cardiovasc Med. 2021 Oct 11;8:720581. doi: 10.3389/fcvm.2021.720581. eCollection 2021.
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. 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, 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. Fgf21 administration effectively suppressed atrial remodeling by reducing oxidative stress, which provides a novel therapeutic insight for AF.
心房的结构和电变化，也称为心房重构，是心房颤动（AF）的主要特征。成纤维细胞生长因子21（Fgf21）是一种重要的内分泌因子，已被证明在心血管疾病中起重要作用。然而，Fgf21对心房重构的影响尚未得到研究。本研究的目的是评估Fgf21对心房重构的影响。成年小鼠接受血管紧张素II治疗，并随机给予或不给予Fgf21，持续2周。通过电刺激和光学标测技术评估房颤易感性。在此，我们发现给予Fgf21可减弱心房颤动/房性心动过速（AF/AT）的诱发率，提高小鼠心房的心外膜传导速度。机制上，Fgf21可预防心房纤维化并降低心房的氧化应激。同样，研究还表明，Fgf21可阻断成纤维细胞中Tgf-β诱导的胶原蛋白上调，并减轻快速起搏诱导的氧化应激，包括心房肌细胞中的活性氧（ROS）、Tgf-β和氧化钙调蛋白激酶II。我们进一步发现，Fgf21通过诱导抗氧化基因如SOD2和UCP3来减轻氧化应激。Fgf21还改善了快速起搏诱导的肌原纤维降解、L型钙通道下调和p-RyR2上调，这表明Fgf21对心房的结构和电重构具有保护作用。此外，Nrf2被确定为Fgf21的下游，并部分介导Fgf21诱导的心房肌细胞抗氧化基因表达。给予Fgf21可通过降低氧化应激有效抑制心房重构，这为房颤提供了一种新的治疗思路。
