title: Relaxin inhibits cardiac fibrosis and endothelial-mesenchymal transition via the Notch pathway.
abstract: BACKGROUND
  Relaxin (RLX) can prevent cardiac fibrosis. We aimed to investigate the possible mechanism and signal transduction pathway of RLX inhibiting cardiac fibrosis.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  RLX may inhibit the cardiac fibrosis via EndMT by Notch-mediated signaling.
authors: Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: X
authors: X
authors: Zhou
authors: Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: X
authors: X
authors: Chen
authors: Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: J J
authors: JJ
authors: Cai
authors: Department of Clinical Laboratory, Wenzhou Central Hospital, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: L Z
authors: LZ
authors: Chen
authors: Institute of Hypoxia Medicine, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: Y S
authors: YS
authors: Gong
authors: Department of Respiratory Medicine, Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: L X
authors: LX
authors: Wang
authors: Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: Z
authors: Z
authors: Gao
authors: Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: H Q
authors: HQ
authors: Zhang
authors: Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: W J
authors: WJ
authors: Huang
authors: Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
authors: H
authors: H
authors: Zhou
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005355:Fibrosis; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007545:Isoproterenol; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012065:Relaxin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D012065:Relaxin; D003094:Collagen; D007545:Isoproterenol
keywords: Notch; endothelial to mesenchymal transition; myocardial fibrosis; relaxin; transforming growth factor β