Stimulation of Adenosine A2B Receptor Inhibits Endothelin-1-Induced Cardiac Fibroblast Proliferation and α-Smooth Muscle Actin Synthesis Through the cAMP/Epac/PI3K/Akt-Signaling Pathway.

Sarawuth Phosri,Motohiro Nishida,Warisara Parichatikanond,Supachoke Mangmool,Akiyuki Nishimura,Ajaree Arieyawong,Kwanchai Bunrukchai

doi:10.3389/fphar.2017.00428

Abstract

Background and Purpose: Cardiac fibrosis is characterized by an increase in fibroblast proliferation, overproduction of extracellular matrix proteins, and the formation of myofibroblast that express α-smooth muscle actin (α-SMA). Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac fibrosis. Overstimulation of endothelin receptors induced cell proliferation, collagen synthesis, and α-SMA expression in cardiac fibroblasts. Although adenosine was shown to have cardioprotective effects, the molecular mechanisms by which adenosine A2 receptor inhibit ET-1-induced fibroblast proliferation and α-SMA expression in cardiac fibroblasts are not clearly identified.Experimental Approach: This study aimed at evaluating the mechanisms of cardioprotective effects of adenosine receptor agonist in rat cardiac fibroblast by measurement of cell proliferation, and mRNA and protein levels of α-SMA.Key results: Stimulation of adenosine subtype 2B (A2B) receptor resulted in the inhibition of ET-1-induced fibroblast proliferation, and a reduction of ET-1-induced α-SMA expression that is dependent on cAMP/Epac/PI3K/Akt signaling pathways in cardiac fibroblasts. The data in this study confirm a critical role for Epac signaling on A2B receptor-mediated inhibition of ET-1-induced cardiac fibrosis via PI3K and Akt activation.Conclusion and Implications: This is the first work reporting a novel signaling pathway for the inhibition of ET-1-induced cardiac fibrosis mediated through the A2B receptor. Thus, A2B receptor agonists represent a promising perspective as therapeutic targets for the prevention of cardiac fibrosis.

Highlights

Cardiac fibrosis is one of the major causes of heart failure and contributes to the abnormality of cardiac functions
Because A2 receptor agonists (e.g., NECA, and adenosine) were shown to increase cyclic adenosine monophosphate (cAMP) levels in the heart and cAMP is a regulator of fibroblast functions (Insel et al, 2012), we investigated whether the inhibition of ET-1-induced cardiac fibrosis by CV1808 is dependent on cAMP
Pretreatment with CV1808 inhibited ET-1-induced cell proliferation in a dose-dependent manner that shown the maximal effect at Stimulation of A2 Receptors Inhibits ET-1-Induced Cardiac Fibrosis in a protein kinase A (PKA)-Independent, exchange protein directly activated by cAMP (Epac)-Dependent Manner

Summary

Introduction

Cardiac fibrosis is one of the major causes of heart failure and contributes to the abnormality of cardiac functions. Treatment with ET-1 induced cell proliferation, collagen synthesis, and α-SMA expression as a hallmark of cardiac fibrosis (Nishida et al, 2007). Cardiac fibrosis is characterized by an increase in fibroblast proliferation, overproduction of extracellular matrix proteins, and the formation of myofibroblast that express α-smooth muscle actin (α-SMA). Overstimulation of endothelin receptors induced cell proliferation, collagen synthesis, and α-SMA expression in cardiac fibroblasts. Experimental Approach: This study aimed at evaluating the mechanisms of cardioprotective effects of adenosine receptor agonist in rat cardiac fibroblast by measurement of cell proliferation, and mRNA and protein levels of α-SMA Adenosine was shown to have cardioprotective effects, the molecular mechanisms by which adenosine A2 receptor inhibit ET-1-induced fibroblast proliferation and α-SMA expression in cardiac fibroblasts are not clearly identified.

Objectives

Methods

Results

Conclusion