title: Anti-Fibrosis Effect of Relaxin and Spironolactone Combined on Isoprenaline-Induced Myocardial Fibrosis in Rats via Inhibition of Endothelial-Mesenchymal Transition.
abstract: BACKGROUND
  The effect of relaxin and spironolactone combined on myocardial fibrosis has not been reported. Thus, we investigated the effect of the combined therapy on isoprenaline-induced myocardial fibrosis and the mechanism.
  
  
  METHODS
  Rats were injected subcutaneously with isoprenaline to induce myocardial fibrosis and underwent subcutaneous injection with relaxin (2 µg·kg-1·d-1) and given a gavage of spironolactone (30 mg·kg-1·d-1) alone or combined for 14 days. In vitro, the endothelial-mesenchymal transition was induced with transforming growth factor β (TGF-β) in human umbilical vein endothelial cells (HUVECs) pretreated with relaxin, 200 ng/ml, and/or spironolactone, 1uM.
  
  
  RESULTS
  Relaxin and spironolactone used alone or combined improved cardiac function and decreased cardiac weight indices; reduced fibrous tissue proliferation; reduced levels of type I and III collagen; decreased the expression of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1), and increased the expression of cluster of differentiation-31 (CD31) in rats with isoprenaline-induced myocardial fibrosis. In vitro, compared with TGF-β treatment, relaxin and spironolactone used alone or combined with TGF-β decreased cell mobility, α-SMA and vimentin levels but increased vascular endothelial cadherin (VE-cadherin) and endothelial CD31levels. Especially, combined therapy had more remarkable effect than relaxin and spironolactone used alone both in vitro and in vivo.
  
  
  CONCLUSIONS
  Relaxin and spironolactone combined affected isoprenaline-induced myocardial fibrosis in rats that the mechanism might be inhibition of the cardiac endothelial-mesenchymal transition.
authors.forename: Jiejie
authors.initials: J
authors.lastname: Cai
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Xingxing
authors.initials: X
authors.lastname: Chen
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Chen
authors.forename: Gaoshu
authors.initials: G
authors.lastname: Zheng
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.forename: Xi
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004719:Endomyocardial Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007545:Isoproterenol; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012065:Relaxin / Q000494:pharmacology*; D013148:Spironolactone / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D002316:Cardiotonic Agents; D024042:Collagen Type I; D024061:Collagen Type III; D007545:Isoproterenol; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012065:Relaxin; D013148:Spironolactone; D016212:Transforming Growth Factor beta; D014746:Vimentin; D000099152:Cadherin 5; C498862:Acta2 protein, rat
keywords: Cardiac fibrosis; Endothelial-mesenchymal transition; Relaxin; Spironolactone; Transforming growth factor β