title: Hepatocyte growth factor reduces cardiac fibrosis by inhibiting endothelial-mesenchymal transition.
abstract: The purpose of this study was to investigate the effect of hepatocyte growth factor (HGF) on the pathogenesis of cardiac fibrosis induced by pressure overload in mice. Although cardiac fibrosis is attributed to excess pathological deposition of extracellular matrix components, the mechanism remains unclear. Recent reports revealed that α-smooth muscle actin-expressing myofibroblasts are primarily responsible for fibrosis. It is believed that myofibroblasts are differentiated from resident fibroblasts, whereas the transformation of vascular endothelial cells into myofibroblasts, known as endothelial-mesenchymal transition, has been suggested to be intimately associated with perivascular fibrosis. Thus, we hypothesized that HGF prevents cardiac fibrosis by blocking these pathways. We analyzed the pressure-overloaded HGF-transgenic mouse model made by transverse aortic constriction. Human coronary artery endothelial cells and human cardiac fibroblasts were examined in vitro after being treated with transforming growth factor-β1 or angiotensin II with or without HGF. The amount of cardiac fibrosis significantly decreased in pressure-overloaded HGF-transgenic mice compared with pressure-overloaded nontransgenic controls, particularly in the perivascular region. This was accompanied by a reduction in the expression levels of fibrosis-related genes and by significant preservation of echocardiographic measurements of cardiac function in the HGF-transgenic mice (P<0.05). The survival rate 2 months after transverse aortic constriction was higher by 45% (P<0.05). HGF inhibited the differentiation of human coronary artery endothelial cells into myofibroblasts induced by transforming growth factor-β1 and the phenotypic conversion of human cardiac fibroblasts into myofibroblasts. We conclude that HGF reduced cardiac fibrosis by inhibiting endothelial-mesenchymal transition and the transformation of fibroblasts into myofibroblasts.
authors.affiliation: Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Okayama
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.forename: Norio
authors.initials: N
authors.lastname: Dosaka
authors.forename: Kazuma
authors.initials: K
authors.lastname: Iekushi
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kusunoki
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwabayashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011897:Random Allocation; D012016:Reference Values; D015996:Survival Rate
chemical_list: D017228:Hepatocyte Growth Factor