Apelin Inhibits Angiotensin II-Induced Atrial Fibrosis and Atrial Fibrillation via TGF-β1/Smad2/α-SMA Pathway.

Wenkui Lv,Wenkui Lv,Wen Qin,Hongli Wang,Hongli Wang,Baopeng Tang,Baopeng Tang,Xinchun Cheng,Xianhui Zhou,Xianhui Zhou,Ling Zhang,Ling Zhang

doi:10.3389/fphys.2020.583570

Abstract

BackgroundAngiotensin II (Ang II) could promote the development of atrial fibrosis in atrial fibrillation (AF). Apelin can inhibit the occurrence of myocardial fibrosis. However, the effect of apelin on Ang II-induced atrial fibrosis and subsequent AF still remains unknown.ObjectiveIn the present study, we examined the effect of apelin on the suppression of atrial fibrosis and subsequent AF, and investigated its underlying mechanisms.MethodsSprague-Dawley rats were treated for 2 weeks with Ang II (1080 μg/kg/24 h) and apelin-13 (140 μg/kg/24 h) using implantable mini-pumps. The incidence of AF induced by atrial pacing was determined. Atrial electrophysiological mapping was recorded by a 32-electrode microelectrode array. Blood was collected to measure the levels of Ang II and apelin. Atrial tissue samples were preserved to assess the pathohistological changes, DDR2 and α-SMA co-staining were performed, and the protein expression of Smad2 phosphorylation was evaluated.ResultsApelin significantly inhibited Ang II-induced atrial fibrosis (HE:1.45 ± 0.11 vs 6.12 ± 0.16, P < 0.001; Masson:1.49 ± 0.25 vs 8.15 ± 0.23, P < 0.001; Picrosirius Red:1.98 ± 0.64 vs 9.59 ± 0.56, P < 0.001, respectively) and decreased the vulnerability of AF (inducibility of AF: z = −4.40, P < 0.001; total AF duration: z = −4.349, P < 0.001). Left atrial epicardial mapping studies demonstrated preservation of atrial conduction homogeneity by apelin. The protective effects of apelin from fibrotic remodeling were mediated by suppression of Smad2-dependent fibrosis.ConclusionApelin potently inhibited Ang II-induced atrial fibrosis and subsequent vulnerability to AF induction via suppression TGF-β/Smad2/α-SMA pathway. Our results indicated that apelin might be an effective up-stream therapy for atrial fibrosis and AF.

Highlights

Atrial fibrillation (AF) is one of the most common arrhythmias, with high incidence rate and mortality
Co-staining of atrial tissues with DDR2 and α-SMA revealed a significant increase in the fibroblasts in Angiotensin II (Ang II) group compared with the control group, whereas this effect was almost completely blunted in the Ang II + apelin group (Figure 4A)
Ang II plasma levels were significantly higher in both Ang II and Ang II + apelin groups compared with the corresponding group before administration

Summary

Introduction

Atrial fibrillation (AF) is one of the most common arrhythmias, with high incidence rate and mortality. Angiotensin II (Ang II) can induce the proliferation of fibroblasts and the development of atrial fibrosis (Dzeshka et al, 2015; Hu et al, 2015). More and more evidences show that apelin plays a protective role in the development of cardiovascular diseases (Cao et al, 2015; Zhong et al, 2017). Previous studies have found that apelin could inhibit the development of myocardial fibrosis (Huang et al, 2016; Xu et al, 2016). The effect and underlying mechanisms of apelin on AF and atrial fibrosis remain unclear. Angiotensin II (Ang II) could promote the development of atrial fibrosis in atrial fibrillation (AF). Apelin can inhibit the occurrence of myocardial fibrosis. The effect of apelin on Ang II-induced atrial fibrosis and subsequent AF still remains unknown

Methods

Results

Conclusion