ANGPTL4 Attenuates Ang II-Induced Atrial Fibrillation and Fibrosis in Mice via PPAR Pathway.

Xi Zhu,Zhongping Ning,Xiaogang Zhang,Luoning Zhu,Xinpeng Cong,Pasquale Mone

doi:10.1155/2021/9935310

Xi Zhu, Zhongping Ning + Show 4 more

Open Access

https://doi.org/10.1155/2021/9935310

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Abstract

Atrial fibrillation (AF) is the more significant portion of arrhythmia in clinical practice, with inflammation and fibrosis as its central pathological mechanisms. This study aimed to investigate angiopoietin-like 4 (ANGPTL4) effects on angiotensin II- (Ang II-) induced AF and its related pathophysiological mechanisms. C57BL/6J mice were randomized and divided into three groups: the control group, the Ang II group, and the ANGPTL4 group (Ang II with ANGPTL4 treatment). Mice were infused with Ang II (2000 ng/kg/min) and were administrated with recombinant human ANGPTL4 (rhANGPTL4, 20 μg/kg/day) for 3 weeks. The fibrosis was evaluated with Masson's trichrome staining in the atrial myocardium. mRNA levels of IL-1β, IL-6, collagen I, and collagen III were measured using real-time qRT-PCR. Protein levels of PPARα, PPARγ, CPT-1, and SIRT3 were measured using Western blotting. Compared to the control group, the mice infused with Ang II showed electrocardiogram characteristics of AF, and this effect was markedly attenuated in ANGPTL4-treated mice. ANGPTL4 also reversed the increase in cardiomyocyte apoptosis, inflammation, interstitial collagen fraction, and collagen gene expression in mice with Ang II. Mechanistically, ANGPTL4 inhibited the activation of several fatty acid metabolism-related proteins, including PPARα, PPARγ, and CPT-1, and the expression of SIRT3 protein in atrial tissues. In conclusion, ANGPTL4 attenuates Ang II-induced AF and atrial fibrosis by modulation in the SIRT3, PPARα, and PPARγ signaling pathways.

Highlights

Atrial fibrillation (AF) is a persistent arrhythmia that originates from the abnormal atrial matrix and has a variety of inducing factors, such as heart failure, diabetes, and hypertension [1]. e pathogenesis of atrial fibrillation is complex
Increased atrial fibrosis can be observed in the extracellular matrix (ECM) of atrial tissue of animal models and case biopsies of heart failure [3, 4]. e main manifestation of atrial fibrosis is ECM remodeling. e ECM provides stable support for myocardial cells and maintains the stability of myocardial cell structure and plays an important role in the signal transduction between myocardial cells [5]. erefore, atrial fibrosis is a key pathological process of AF, and reducing atrial fibrosis can effectively suppress the susceptibility to AF in animal models [6]
To investigate the role of Angiopoietin-like 4 (ANGPTL4) in regulating AF development, the electrocardiogram was recorded in mice infused with Ang II with or without recombinant human ANGPTL4 (20 μg/kg/ day)

Summary

Introduction

Atrial fibrillation (AF) is a persistent arrhythmia that originates from the abnormal atrial matrix and has a variety of inducing factors, such as heart failure, diabetes, and hypertension [1]. e pathogenesis of atrial fibrillation is complex. Recent studies have shown that ANGPTL4 can regulate tumorigenesis, angiogenesis, vascular permeability, lipid metabolism, glucose, energy homeostasis, cell differentiation, wound healing, inflammatory response, and redox reaction. Physiological conditions such as fasting, hypoxia, pregnancy, lactation, and adipocyte differentiation lead to upregulation of ANGPTL4 expression. Studies showed that overexpression of ANGPTL4 decreases LPL activity and increases circulating triglyceride levels. Free fatty acids can inhibit LPL and protect the myocardium by activating PPAR β/δ and inducing ANGPTL4 expression [10]. Is study tested the hypothesis that ANGPTL4 can prevent atrial remodeling and fibrosis in angiotensin II(Ang II-) induced mice model, potentially through modulation of the fatty acid metabolism signaling pathway

Materials and Methods

Results

RR Interval

Relative protein expression