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Published on: June 3, 2018
Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyopathic hamster hearts
Teruya Nakamura1, Kunio Matsumoto, Shinya Mizuno
1Division of Molecular Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. nakamura@onbich.med.osaka-u.ac.jp
Insights
Hepatocyte growth factor (HGF) deficiency worsens dilated cardiomyopathy, leading to fibrosis and hypertrophy. Supplementing HGF improved cardiac function and reduced fibrosis in hamster models, suggesting HGF therapy potential.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Regenerative Medicine
Background:
- Cardiomyopathy involves myocardial structural remodeling, leading to functional impairment.
- Hepatocyte growth factor (HGF) exhibits cytoprotective effects and benefits in acute heart injury.
- Dilated cardiomyopathy is characterized by cardiac hypertrophy, fibrosis, and dilatation.
Purpose of the Study:
- To investigate the role of HGF in the pathophysiology of dilated cardiomyopathy.
- To evaluate the therapeutic potential of HGF in a genetic model of dilated cardiomyopathy.
Main Methods:
- Utilized delta-sarcoglycan-deficient Syrian hamsters (TO-2 model) with induced cardiomyopathy.
- Administered recombinant human HGF to late-stage cardiomyopathic hamsters for 3 weeks.
- Assessed cardiac function, fibrosis, hypertrophy, and apoptosis markers via molecular and histological analyses.
Main Results:
- Downregulated HGF levels correlated with increased myocardial fibrosis and hypertrophy in cardiomyopathic hamsters.
- HGF treatment significantly suppressed cardiac fibrosis, TGF-beta1, and type I collagen expression.
- HGF administration reduced myocardial hypertrophy, cardiomyocyte apoptosis, and atrial natriuretic polypeptide expression.
- HGF treatment led to improved cardiac function in late-stage dilated cardiomyopathy.
Conclusions:
- Decreased endogenous HGF contributes to cardiac hypertrophy and fibrosis in dilated cardiomyopathy.
- Exogenous HGF demonstrates therapeutic benefits in dilated cardiomyopathy, even with late-stage intervention.
- HGF holds promise as a therapeutic agent for dilated cardiomyopathy.
Abstract:
Structural remodeling of the myocardium, including myocyte hypertrophy, myocardial fibrosis, and dilatation, drives functional impairment in various forms of acquired and hereditary cardiomyopathy. Using cardiomyopathic Syrian hamsters with a genetic defect in delta-sarcoglycan, we investigated the potential involvement of hepatocyte growth factor (HGF) in the pathophysiology and therapeutics related to dilated cardiomyopathy, because HGF has previously been shown to be cytoprotective and to have benefits in acute heart injury. Late-stage TO-2 cardiomyopathic hamsters showed severe cardiac dysfunction and fibrosis, accompanied by increases in myocardial expression of transforming growth factor-beta1 (TGF-beta1), a growth factor responsible for tissue fibrosis. Conversely, HGF was downregulated in late-stage myopathic hearts. Treatment with recombinant human HGF for 3 wk suppressed cardiac fibrosis, accompanied by a decreased expression of TGF-beta1 and type I collagen. Suppression of TGF-beta1 and type I collagen by HGF was also shown in cultured cardiac myofibroblasts. Likewise, HGF suppressed myocardial hypertrophy, apoptosis in cardiomyocytes, and expression of atrial natriuretic polypeptide, a molecular marker of hypertrophy. Importantly, downregulation of the fibrogenic and hypertrophic genes by HGF treatment was associated with improved cardiac function. Thus the decrease in endogenous HGF levels may participate in the susceptibility of cardiac tissue to hypertrophy and fibrosis, and exogenous HGF led to therapeutic benefits in case of dilated cardiomyopathy in this model, even at the late-stage treatment.
