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.