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Inhibitory Effects of Enalaprilat on Rat Cardiac Fibroblast Proliferation via ROS/P38MAPK/TGF-β1 Signaling Pathway
Department of Cardiology, First Clinic Hospital Of Jilin University, Changchun 130021, China
Department of Cardiology, Affiliated Hospital of Beihua University, Jilin 132011, China
Department of Pharmacology, College of Pharmacy, Beihua University, Jilin 132013, China
* Authors to whom correspondence should be addressed.
Received: 8 January 2012; in revised form: 23 February 2012 / Accepted: 29 February 2012 / Published: 6 March 2012
Abstract: Enalaprilat (Ena.), an angiotensin II (Ang II) converting enzyme inhibitor (ACEI), can produce some therapeutic effects on hypertension, ventricular hypertrophy and myocardial remodeling in clinic, but its precise mechanism, especially its signaling pathways remain elusive. In this study, cardiac fibroblasts (CFb) was isolated by the trypsin digestion method; a BrdU proliferation assay was adopted to determine cell proliferation; an immunofluorescence assay was used to measure intracellular reactive oxygen species (ROS); immunocytochemistry staining and Western blotting assay were used to detect phosphorylated p38 mitogen activated protein kinase (p-p38MAPK) and transforming growth factor-β1 (TGF-β1) protein expression, respectively. The results showed that Ang II (10–7 M) stimulated the cardiac fibroblast proliferation which was inhibited by NAC (an antioxidant), SB203580 (a p38MAPK inhibitor) or enalaprilat; Ang II caused an burst of intracellular ROS level within thirty minutes, an increase in p-p38MAPK (3.6-fold of that in the control group), as well as an elevation of TGF-β1 meantime; NAC, an antioxidant, and enalaprilat treatment attenuated cardiac fibroblast proliferation induced by Ang II and decreased ROS and p-p38MAPK protein levels in rat cardiac fibroblast; SB203580 lowered TGF-β1 protein expression in rats’ CFb in a dose-dependent manner. It could be concluded that enalaprilat can inhibit the cardiac fibroblast proliferation induced by Ang II via blocking ROS/P38MAPK/TGF-β1 signaling pathways and the study provides a theoretical proof for the application of ACEIs in treating myocardial fibrosis and discovering the primary mechanism through which ACEIs inhibit CFb proliferation.
Keywords: enalaprilat; angiotensin II; cardiac fibroblast; reactive oxygen species; p38 mitogen activated protein kinase; transforming growth factor-β1
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MDPI and ACS Style
Yu, M.; Zheng, Y.; Sun, H.-X.; Yu, D.-J. Inhibitory Effects of Enalaprilat on Rat Cardiac Fibroblast Proliferation via ROS/P38MAPK/TGF-β1 Signaling Pathway. Molecules 2012, 17, 2738-2751.
Yu M, Zheng Y, Sun H-X, Yu D-J. Inhibitory Effects of Enalaprilat on Rat Cardiac Fibroblast Proliferation via ROS/P38MAPK/TGF-β1 Signaling Pathway. Molecules. 2012; 17(3):2738-2751.
Yu, Min; Zheng, Yang; Sun, Hong-Xia; Yu, Du-Juan. 2012. "Inhibitory Effects of Enalaprilat on Rat Cardiac Fibroblast Proliferation via ROS/P38MAPK/TGF-β1 Signaling Pathway." Molecules 17, no. 3: 2738-2751.