Abstract
The purpose of the present study was to study the impacts of eplerenone (EPL), an antagonist of mineralocorticoid receptors (MR), on atrial fibrosis in a mouse model with selective fibrosis in the atrium, and to explore the possible mechanisms. Using mutant TGF-β1 transgenic (Tx) mice, we first demonstrated that EPL inhibited atrial fibrosis specifically and decreased macrophage accumulation in the atria of these mice. Results from immunohistochemistry and western blotting showed that EPL attenuated protein expression of fibrosis-related molecules such as connective tissue growth factor (CTGF) and fibronectin in the atria of Tx mice. In culture, EPL inhibited gene expression of fibrosis-related molecules such as fibronectin, α-SMA, and CTGF in TGF-β1-stimulated atrial fibroblasts. Finally, using a co-culture system, we showed that TGF-β1-stimulated atrial fibroblasts induced migration of macrophages and this was blocked by EPL. EPL also blocked TGF-β1-induced gene expression of intedeukin-6 (IL-6) in atrial fibroblasts. Therefore, we conclude that EPL attenuated atrial fibrosis and macrophage infiltration in Tx mice. TGF-β1 and IL-6 were involved in the impacts of EPL on activation of atrial fibroblasts and interactions between fibroblasts and macrophages.
Highlights
Atrial fibrillation (AF) is the most common type of arrhythmia in clinical practice and posts great challenges to medical treatment (Allessie et al, 2002; Nattel, 2002)
Atrial fibrosis is a hallmark of atrial structural remodeling that critically contributes to the occurrence and maintenance of AF (Burstein and Nattel, 2008)
We aim to investigate the effects of mineralocorticoid receptors (MR) antagonist on atrial fibrosis and macrophages infiltration using MHC-transforming growth factor (TGF) 1cys33ser transgenic (Tx) mice that have fibrosis in atria selectively and to explore the underlying mechanisms
Summary
Atrial fibrillation (AF) is the most common type of arrhythmia in clinical practice and posts great challenges to medical treatment (Allessie et al, 2002; Nattel, 2002). Targeting atrial fibrosis is an important strategy to treat AF. Renin-angiotensin-aldosterone system plays important roles in atrial fibrosis (Ehrlich et al, 2006; Mayyas et al., 2013). MR antagonists have been shown to inhibit atrial fibrosis in animal models such as myocardial infarction that is accompanied by ventricular fibrosis (Milliez et al, 2005). It has remained unclear whether the impacts of MR antagonists on the atrium are dependent on the ventricular changes
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