Potential contribution of a novel antifibrotic factor, hepatocyte growth factor, to prevention of myocardial fibrosis...

Area of Science:

• Cardiovascular Research
• Fibrosis Pathogenesis
• Molecular Biology

Background:

• Hepatocyte growth factor (HGF) has shown antifibrotic effects in liver and lung injury models.
• Angiotensin II (Ang II) is known to decrease local HGF production, suggesting a link to fibrotic cardiovascular disease.
• Investigating HGF's role in Ang II-mediated fibrosis is crucial for understanding cardiovascular disease pathogenesis.

Purpose of the Study:

• To investigate the role of HGF in Ang II-induced myocardial fibrosis.
• To evaluate the effects of ACE inhibitor and Ang II receptor antagonist on cardiac HGF levels and fibrosis.
• To elucidate the antifibrotic mechanisms involving HGF in cardiovascular injury models.

Main Methods:

• In vitro studies using human and rat cardiac fibroblasts.
• In vivo experiments administering an ACE inhibitor (temocapril) and an Ang II type 1 receptor antagonist (CS-866) to cardiomyopathic hamsters.
• Assessed matrix metalloprotease-1 (MMP-1), urokinase plasminogen activator, transforming growth factor-beta (TGF-beta) mRNA and protein levels, and collagen III mRNA expression.

Main Results:

• HGF increased MMP-1 and urokinase plasminogen activator production in human fibroblasts, attenuating Ang II-induced MMP-1 reduction.
• HGF decreased Ang II-stimulated TGF-beta mRNA and basal TGF-beta protein levels in fibroblasts.
• In vivo, temocapril and CS-866 treatment significantly reduced fibrotic area and increased cardiac HGF concentration and mRNA, while decreasing collagen III mRNA expression.

Conclusions:

• Angiotensin II blockade effectively prevents myocardial fibrosis in a hamster model.
• This prevention is associated with a significant increase in cardiac HGF levels.
• Elevated local HGF expression likely contributes to the antifibrotic action of Ang II blockade in myocardial injury.