Relaxin inhibits cardiac fibrosis and endothelial-mesenchymal transition via the Notch pathway

• Published in: Drug design, development and therapy development and therapy, 2015-01, Vol.9 (default), p.4599-4611
• Main Authors: Zhou, X, Chen, X, Cai, J J, Chen, L Z, Gong, Y S, Wang, L X, Gao, Z, Zhang, H Q, Huang, W J, Zhou, H
• Format: Article
• Language: English
• Subjects: Animals; Cardiomyopathies - drug therapy; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cardiomyopathies - physiopathology; Cell culture; Cell migration; Cell Movement - drug effects; Cells, Cultured; Cellular signal transduction; Collagen; Collagen (type I); Collagen - metabolism; Dipeptides - pharmacology; Disease Models, Animal; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Epithelial-Mesenchymal Transition - drug effects; Fibroblasts; Fibrosis; Growth factors; Health aspects; Heart; Heart diseases; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; Hypoxia; Immunofluorescence; Inhibitors; Isoproterenol; Kinases; Laboratory animals; Levels; Male; Mesenchyme; Microvasculature; Mobility; Morphology; Myocardium; Myocardium - metabolism; Myocardium - pathology; Neovascularization, Physiologic - drug effects; Notch1 protein; Original Research; Properties; Proteins; Rats, Sprague-Dawley; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - metabolism; Relaxin; Relaxin - pharmacology; Rodents; Signal transduction; Signal Transduction - drug effects; Stem cells; Transforming growth factor; Transforming growth factor-b; Umbilical vein; Veins; Ventricular Function, Left - drug effects; Vimentin
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/dddt.s85399

Relaxin (RLX) can prevent cardiac fibrosis. We aimed to investigate the possible mechanism and signal transduction pathway of RLX inhibiting cardiac fibrosis. Isoproterenol (5 mg·kg(-1)·d(-1)) was used to establish the cardiac fibrosis model in rats, which were administered RLX. The cardiac function, related targets of cardiac fibrosis, and endothelial-mesenchymal transition (EndMT) were measured. Transforming growth factor β (TGF-β) was used to induce EndMT in human umbilical vein endothelial cells, which were pretreated with RLX, 200 ng·mL(-1), then with the inhibitor of Notch. Transwell cell migration was used to evaluate cell migration. CD31 and vimentin content was determined by immunofluorescence staining and Western blot analysis. Notch protein level was examined by Western blot analysis. RLX improved cardiac function in rats with cardiac fibrosis; it reduced the content of collagen I and III, increased the microvascular density of the myocardium, and suppressed the EndMT in heart tissue. In vitro, RLX decreased the mobility of human umbilical vein endothelial cells induced by TGF-β, increased the expression of endothelial CD31, and decreased vimentin content. Compared to TGF-β and RLX co-culture alone, TGF-β + RLX + Notch inhibitor increased cell mobility and the EndMT, but decreased the levels of Notch-1, HES-1, and Jagged-1 proteins. RLX may inhibit the cardiac fibrosis via EndMT by Notch-mediated signaling.