Fibroblast Growth Factor 1 Reduces Pulmonary Vein and Atrium Arrhythmogenesis via Modification of Oxidative Stress and Sodium/Calcium Homeostasis.

Yen-Yu Lu,Shih-Yu Huang,Yung-Kuo Lin,Yu-Hsun Kao,Yi-Jen Chen,Chen-Chuan Cheng,Shih-Ann Chen,Satoshi Higa,Yao-Chang Chen

doi:10.3389/fcvm.2021.813589

Abstract

RationaleAtrial fibrillation is a critical health burden. Targeting calcium (Ca2+) dysregulation and oxidative stress are potential upstream therapeutic strategies. Fibroblast growth factor (FGF) 1 can modulate Ca2+ homeostasis and has antioxidant activity. The aim of this study was to investigate whether FGF1 has anti-arrhythmic potential through modulating Ca2+ homeostasis and antioxidant activity of pulmonary vein (PV) and left atrium (LA) myocytes.MethodsPatch clamp, western blotting, confocal microscopy, cellular and mitochondrial oxidative stress studies were performed in isolated rabbit PV and LA myocytes treated with or without FGF1 (1 and 10 ng/mL). Conventional microelectrodes were used to record electrical activity in isolated rabbit PV and LA tissue preparations with and without FGF1 (3 μg/kg, i.v.).ResultsFGF1-treated rabbits had a slower heart rate than that observed in controls. PV and LA tissues in FGF1-treated rabbits had slower beating rates and longer action potential duration than those observed in controls. Isoproterenol (1 μM)-treated PV and LA tissues in the FGF1-treated rabbits showed less changes in the increased beating rate and a lower incidence of tachypacing (20 Hz)-induced burst firing than those observed in controls. FGF1 (10 ng/mL)-treated PV and LA myocytes had less oxidative stress and Ca2+ transient than those observed in controls. Compared to controls, FGF1 (10 ng/mL) decreased INa−L in PV myocytes and lowered Ito, IKr−tail in LA myocytes. Protein kinase C (PKC)ε inhibition abolished the effects of FGF1 on the ionic currents of LA and PV myocytes.ConclusionFGF1 changes PV and LA electrophysiological characteristics possibly via modulating oxidative stress, Na+/Ca2+ homeostasis, and the PKCε pathway.

Highlights

Fibroblast growth factor (FGF) 1, a signaling protein secreted mainly in the paracrine system, may be produced by cardiomyocytes [1]
pulmonary vein (PV) and left atrium (LA) tissues in FGF1-treated rabbits had slower beating rates and longer action potential duration than those observed in controls
FGF1 (10 ng/mL)-treated PV and LA myocytes had less oxidative stress and Ca2+ transient than those observed in controls

Summary

Introduction

Fibroblast growth factor (FGF) 1, a signaling protein secreted mainly in the paracrine system, may be produced by cardiomyocytes [1]. FGF23, a member of the FGF family, has several cardiovascular effects and can directly change cardiac electrical activity [4, 5]. The overexpression of FGF1 may protect against cardiac injury through the FGF receptor (FGFR)mediated signaling and the protein kinase C (PKC)-dependent pathway [3, 6]. The FGF1–FGFR system might play an important role in pulmonary vascular remodeling via chronic inflammation, fibrosis, or heart tissue repair, which has been demonstrated in obstructive lung disease [11, 12]. FGF-1 protects cardiomyocytes from oxidative damage with hydrogen peroxide, which may enhance PV and atrial remodeling in the pathogenesis and perpetuation of AF [13,14,15]. FGF may play a critical role in the pathogenesis of AF, and different FGF subtypes may have discrepant effects on PV and atrial arrhythmogenesis

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