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 regressed fibrosis in liver and pulmonary injury models, HGF may play an important role in the pathogenesis of fibrotic cardiovascular disease. Because angiotensin (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.


RESULTS
In human fibroblasts, HGF significantly increased the production of matrix metalloprotease-1 (MMP-1) and urokinase plasminogen activator, whereas HGF also significantly attenuated the reduction of MMP-1 activity induced by Ang II. In contrast, HGF significantly decreased transforming growth factor (TGF)-beta mRNA stimulated by Ang II, whereas HGF also decreased 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 cardiac concentration and mRNA of HGF were significantly decreased in cardiomyopathic hamsters. In contrast, mRNA expression of collagen III was markedly 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 increase in cardiac HGF. Overall, increase in local HGF expression may participate in the prevention of myocardial injury by Ang II blockade through its antifibrotic action.
Taniyama
Y
Y
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
Morishita
R
R
Nakagami
H
H
Moriguchi
A
A
Sakonjo
H
H
Shokei-Kim
Matsumoto
K
K
Nakamura
T
T
Higaki
J
J
Ogihara
T
T
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000473:pathology*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis / Q000517:prevention & control; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D000068557:Olmesartan Medoxomil; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology; D020257:Ventricular Remodeling
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D013777:Tetrazoles; D013841:Thiazepines; D000804:Angiotensin II; D017228:Hepatocyte Growth Factor; D000068557:Olmesartan Medoxomil; C055603:temocapril hydrochloride; D003094:Collagen; D020781:Matrix Metalloproteinase 1