Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyopathic hamster hearts.

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.

• Authors: Teruya Nakamura, Kunio Matsumoto, Shinya Mizuno, Yoshiki Sawa, Hikaru Matsuda, Toshikazu Nakamura
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 288 Issue 5 Pg. H2131-9 (May 2005) ISSN: 0363-6135 [Print] United States
• PMID: 15840903 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• TGFB1 protein, human
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Vasoconstrictor Agents
• Angiotensin II
• Hepatocyte Growth Factor
• Proto-Oncogene Proteins c-met

Topics

• Angiotensin II (pharmacology)
• Animals
• CHO Cells
• Cardiomyopathy, Dilated (diagnostic imaging, drug therapy, pathology)
• Cardiomyopathy, Hypertrophic (diagnostic imaging, drug therapy, pathology)
• Cricetinae
• Fibrosis
• Gene Expression (drug effects)
• Hepatocyte Growth Factor (genetics, pharmacology)
• Humans
• Male
• Mesocricetus
• Myocytes, Cardiac (pathology)
• Proto-Oncogene Proteins c-met (metabolism)
• Transforming Growth Factor beta (metabolism)
• Transforming Growth Factor beta1
• Ultrasonography
• Vasoconstrictor Agents (pharmacology)
• Ventricular Remodeling (drug effects)