Hepatocyte Growth Factor Reduces Cardiac Fibrosis by Inhibiting Endothelial-Mesenchymal Transition

Abstract

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 ␣-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 pressureoverloaded 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-␤1 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 (PϽ0.05). The survival rate 2 months after transverse aortic constriction was higher by 45% (PϽ0.05). HGF inhibited the differentiation of human coronary artery endothelial cells into myofibroblasts induced by transforming growth factor-␤1 and the phenotypic conversion of human cardiac fibroblasts into myofibroblasts. We conclude that HGF reduced cardiac fibrosis by inhibiting endothelialmesenchymal transition and the transformation of fibroblasts into myofibroblasts. 1 The number of cardiovascular deaths has been reduced, but in spite of a marked development in recent devices and medicines, cardiovascular disease still impacts the mortality rate in almost all nations.2 Cardiac fibrosis is often present in end-stage heart failure and is caused by various factors, such as ischemia, 3 pressure overload, 4 and cardiomyopathy, 5 so antifibrotic therapy is believed to be beneficial in preventing heart failure. Although fibrosis, which is attributed to an excess deposition of extracellular matrix (ECM) components, is one of the most common pathological changes found in various organs, including the heart, the detailed mechanism remains unclear. It is worth noting that myofibroblasts are characterized by ␣-smooth muscle actin (␣-SMA) expression and appear to play a major role in the pathogenesis of fibrosis by secreting numerous cytokines, growth factors, and ECM proteins. 6 Myofibroblasts were originally thought to be differentiated from resident fibroblasts activated by acute or chronic stimuli, such as myocardial infarction and pressure overload. On the other ...

Hepatocyte Growth Factor and Cardiomyopathy in Dialysis Patients

“…4 In our study published in Hypertension, 3 HGF was directly associated with the muscular component of the left ventricle (mean wall thickness and concentric remodeling of the left ventricle) and inversely with the cavitary component (left ventricular end diastolic volume), suggesting a compensatory mechanism aimed at limiting cardiac fibrosis in these patients. Experimental data by Okayama et al 1 showing that HGF limits myocardial fibrosis in a pressure-overload model suggests that the direct association of circulating HGF with concentric left ventricular geometry observed in our study may underlie resistance to the cardioprotective effect of HGF. Resistance to potentially protective endogenous factors plays a role in cardiomyopathy in kidney failure.…”

“…This pattern 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. 1 These intriguing experimental data suggest that an increased expression of HGF may limit myocardial fibrosis in human cardiomyopathies with a relevant pressureoverload component. Pressure-overload and volume expansion are pervasive in patients with kidney failure on dialysis, a population with an exceedingly high risk for death and cardiovascular events, particularly heart failure.…”

FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling

“…Endothelial mitogens inhibit EndMT (Medici and Kalluri, 2012;Okayama et al, 2012;Ichise et al, 2014;Zhang et al, 2015). We questioned whether this inhibitory effect might be (in part) due to the induction of miR-20a.…”

“…Moreover, although multiple receptor tyrosine kinases (RTKs) are implemented in the protection against EndMT (Medici et al, 2010;Okayama et al, 2012), only FGF2 signaling induced miR20a. RTKs depend on scaffold molecules that organize their downstream effects.…”

Potential Target Molecules in Diabetic Cardiomyopathy: Hepatocyte Growth Factor (HGF) and Ryanodine Receptor 2 (RyR2)

“…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 pattern 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 [59]. In dogs with intracoronary microembolization-induced heart failure, intramyocardial injections of HGF naked DNA plasmid attenuated the expression abnormalities of the SR Ca 2+ -cycling proteins, improved regional and global left ventricular function and prevented progressive LV remodeling [60].…”