Eplerenone Prevents Atrial Fibrosis via the TGF-β Signaling Pathway

Abstract

Objectives: Eplerenone (EPL), an antagonist of the mineralocorticoid receptor, is beneficial for atrial fibrillation and atrial fibrosis. However, the underlying mechanism remains less well known. We aimed to investigate the effect of EPL on atrial fibrosis using a mouse with selective atrial fibrosis and to explore the underlying mechanisms. Methods: EPL-treated MHC-TGFcys³³ser transgenic mice that have selective atrial fibrosis (Tx+EPL mice), as well as control mice, were used for in vivo studies including histological analyses, Western blotting, and qRT-PCR studies. TGF-β₁-stimulated atrial fibroblasts were treated with EPL or vehicle for the in vitro studies including Western blotting and qRT-PCR studies. In addition, Smad7 siRNA was used to knock down Smad7. Results: EPL inhibited atrial fibrosis in the Tx mice. In addition, EPL suppressed the expression of fibrosis-related molecules induced by TGF-β₁ in vivo and in vitro. This occurred in concert with a downregulation of Smad7 protein expression and an upregulation of p-Smad2/3 protein expression. In addition, knockdown of Smad7 by siRNA abolished the protective roles of EPL. Conclusions: EPL inhibited atrial fibrosis in Tx mice. The underlying mechanism may involve increased protein expression of Smad7, which enhances the inhibitory feedback regulation of TGF-β₁/Smad signaling.

Mineralocorticoid Receptor Antagonists Eplerenone and Spironolactone Modify Adrenal Cortex Morphology and Physiology

“…Previous studies found that spironolactone reduced the content of the collagen fiber content in other tissues, such as in the myocardium [38,39]. Although, previous studies reported that eplerenone had similar anti-fibrotic effects on the myocardial tissue [40], in our study, eplerenone treatment did not significantly reduce adrenal capsule width. The mechanisms behind the spironolactone effect on the adrenal capsule are still unknown; however, although it is positive in the myocardium context, the consequences of a reduction of the connective tissue of the adrenal gland may compromise the gland structure.…”

Left atrial fibrosis in atrial fibrillation: Mechanisms, clinical evaluation and management

“…The RAAS is progressively considered a critical player in cardiac fibrosis development. 53 Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) [54][55][56][57][58][59] and mineralocorticoid receptor antagonists [60][61][62][63] can reduce atrial fibrosis progression and AF susceptibility, as demonstrated by multiple experimental studies (Table 1). 64 Retrospective trials and meta-analyses of randomized studies demonstrated that administration of ACEIs or ARBs with ACEIs/ARBs of these diseases may have been confounded by indications.…”

Involvement of Smad3 pathway in atrial fibrosis induced by elevated hydrostatic pressure

“…Furthermore, inhibition of TGF‐β1/Smad3 signaling pathway can prevent cardiac reconstruction and release diastolic cardiac dysfunction (Ramos‐Mondragon, Galindo, & Avila, ). Over‐expression of TGF‐β1 is related to atrial fibrosis much more than ventricular fibrosis (Du et al, ). According to our results, compared to the Wistar rats, the protein levels of Smad3 and p‐Smad3 increased significantly in atrium lysates from SHRs.…”