Potential contribution of a novel antifibrotic factor, hepatocyte growth factor, to prevention of myocardial fibrosis by angiotensin II blockade in cardiomyopathic hamsters

Background-Because hepatocyte growth factor (HGF) prevented and/or regresse d fibrosis in liver and pulmonary injury models, HGF may play an important role in the pathogenesis of fibrotic cardiovascular disease. Because angiot ensin (Ang) II significantly decreased local HGF production, we performed ( 1) in vitro experiments using fibroblasts and (2) administration of an ACE inhibitor (temocapril) and an Ang II type 1 receptor antagonist (CS-866) to cardiomyopathic hamsters. Methods and Results-In human fibroblasts, HGF significantly increased the p roduction of matrix metalloprotease-1 (MMP-1) and urokinase plasminogen act ivator, whereas HGF also significantly attenuated the reduction of MMP-1 ac tivity induced by Ang II. In contrast, HGF significantly decreased transfor ming growth factor (TGF)-beta mRNA stimulated by Ang II, whereas HGF also d ecreased basal TGF-beta protein level without affecting growth, Similarly, in rat cardiac fibroblasts, HGF inhibited the expression and production of TGF-beta, whereas HGF upregulated its specific receptor, c-met. Conversely, in vivo experiments revealed that administration of temocapril and CS-866 to cardiomyopathic hamsters resulted in a significant decrease in fibrotic area and increase in cardiac HGF concentration and mRNA (P<0.01), whereas c ardiac concentration and mRNA of HGF were significantly decreased in cardio myopathic hamsters, In contrast. mRNA expression of collagen III was marked ly decreased by treatment with temocapril and CS-866. Conclusions-Here, we demonstrated that Ang II blockade prevented myocardial fibrosis in the cardiomyopathic hamster, accompanied by a significant incr ease in cardiac HGF. Overall, increase in local HGF expression may particip ate in the prevention of myocardial injury by Ang II blockade through its a ntifibrotic action.