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
Autor: | Sarawuth Phosri, Ajaree Arieyawong, Kwanchai Bunrukchai, Warisara Parichatikanond, Akiyuki Nishimura, Motohiro Nishida, Supachoke Mangmool |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
medicine.medical_specialty Cardiac fibrosis Epac Biology PI3K A2B receptor 03 medical and health sciences Adenosine A1 receptor 0302 clinical medicine Internal medicine cAMP medicine Pharmacology (medical) Protein kinase B PI3K/AKT/mTOR pathway Original Research Pharmacology Endothelin-1 Akt lcsh:RM1-950 cardiac fibroblast α-SMA medicine.disease Adenosine A3 receptor Adenosine receptor Cell biology 030104 developmental biology Endocrinology lcsh:Therapeutics. Pharmacology 030220 oncology & carcinogenesis Myofibroblast Adenosine A2B receptor |
Zdroj: | Frontiers in Pharmacology, Vol 8 (2017) Frontiers in Pharmacology |
ISSN: | 1663-9812 |
DOI: | 10.3389/fphar.2017.00428 |
Popis: | 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. |
Databáze: | OpenAIRE |
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