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Updated: May 24, 2026
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Hepatocyte growth factor reduces cardiac fibrosis by inhibiting endothelial-mesenchymal transition
Keita Okayama1, Junya Azuma, Norio Dosaka
1Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Insights
Hepatocyte growth factor (HGF) effectively reduces cardiac fibrosis in mice by inhibiting myofibroblast differentiation from both endothelial cells and fibroblasts, preserving heart function and improving survival rates.
Area of Science:
- Cardiovascular Biology
- Fibrosis Research
- Molecular Medicine
Background:
- Cardiac fibrosis, characterized by excessive extracellular matrix deposition, is a key pathological process in heart disease.
- Myofibroblasts, derived from fibroblasts and endothelial-mesenchymal transition, are primary drivers of cardiac fibrosis.
- The precise mechanisms regulating myofibroblast activation and their role in fibrosis pathogenesis require further elucidation.
Purpose of the Study:
- To investigate the therapeutic potential of hepatocyte growth factor (HGF) in mitigating cardiac fibrosis induced by pressure overload.
- To determine if HGF can inhibit the differentiation of endothelial cells and fibroblasts into myofibroblasts, key contributors to fibrosis.
Main Methods:
- Utilized a pressure-overloaded HGF-transgenic mouse model created via transverse aortic constriction.
- Conducted in vitro studies using human coronary artery endothelial cells and human cardiac fibroblasts treated with TGF-β1 or Angiotensin II, with or without HGF.
- Assessed cardiac fibrosis, fibrosis-related gene expression, cardiac function (echocardiography), and survival rates.
Main Results:
- HGF-transgenic mice exhibited significantly reduced cardiac fibrosis, particularly in perivascular regions, compared to controls.
- HGF treatment inhibited transforming growth factor-β1-induced endothelial-mesenchymal transition and fibroblast-to-myofibroblast differentiation in vitro.
- Pressure-overloaded HGF-transgenic mice showed preserved cardiac function and a 45% increase in survival rate post-constriction.
Conclusions:
- Hepatocyte growth factor (HGF) effectively ameliorates cardiac fibrosis by suppressing endothelial-mesenchymal transition and fibroblast activation.
- HGF demonstrates significant cardioprotective effects, improving cardiac function and survival in a pressure overload model.
- These findings highlight HGF as a potential therapeutic agent for treating cardiac fibrosis and related heart conditions.
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.
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