期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 789, 期 -, 页码 319-327出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2016.07.053
关键词
Activin A; MAPKs; ALK4; Proliferation and differentiation; Cardiac fibrosis; Cardiac fibroblasts
资金
- National Key Basic Research Development Program of China (The 973 Program) [2012CB518604]
- Natural Natural Science Foundation of China [81200139]
- Fundamental Research Funds for the Central Universities, China [2014302020201]
- Natural Science Foundation of Hubei Province, China [2013CFA117]
Activin A is a key regulator of cardiac fibrosis. However, little is known about the mechanisms by which it contributes to cardiac fibrosis. Our study explored the effects of activin A on proliferation and differentiation of adult rat cardiac fibroblasts (CFs) via the activin A receptor, activin receptor-like kinase 4 (ALK4). CF proliferation was measured by CCK8 and EdU assays, while differentiation, fibrosis and signaling were measured by western blot analysis of alpha-smooth muscle actin, collagen type I, phosphorylated extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (p38-MAPK) expression. Activin A levels were measured by ELISA and western blot analysis. We demonstrated that CFs express activin A and its expression was significantly enhanced by angiotensin II (Ang II), but follistatin (activin A inhibitor) significantly reversed Ang II-induced activin A upregulation, CF proliferation, differentiation, collagen type I expression as well as ERK1/2 and p38-MAPK pathways activation. Conversely, recombinant activin A largely increased these parameters in both the presence and absence of Ang II. Interestingly, p38-MAPK (SB203580) and ALK4 (SB431542) inhibitors significantly reduced all activin A-mediated responses; however, an ERK1/2 inhibitor (PD98059) could only significantly reduce CF proliferation and collagen type I expression but not differentiation. Importantly, the most significant effects were observed in the presence vs. absence of Ang II. Thus, activin A promotes basal and Ang Il-induced CF proliferation and differentiation via ALK4, and the effects are partly mediated through the ERKI/2 and p38-MAPK pathways. These data suggest that activin A is a potential therapeutic target for cardiac fibrosis. (C) 2016 Elsevier B.V. All rights reserved.
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