Antifibrotic effect of adrenomedullin on coronary adventitia in angiotensin II-induced hypertensive rats.
OBJECTIVE
The extracellular matrix (ECM) determines the structural integrity of the heart and vasculature, participating in cardiovascular remodeling. We previously reported that adrenomedullin (AM) inhibited cellular proliferation and protein synthesis of cardiac fibroblasts; however, the precise mechanisms of AM actions as an antifibrotic factor remain unknown. The purpose of this study was to examine the biological actions of AM against the profibrotic factor angiotensin II (Ang II) in coronary adventitia.


RESULTS
Rats with hypertension induced by Ang II infusion were administered 0.06 mug/kg/min recombinant human AM subcutaneously for 14 days. The AM infusion significantly (p<0.05) reduced the Ang II-induced increase of coronary adventitial fibroblasts expressing Ki-67 and alpha-smooth muscle actin (alpha-SMA) in the left ventricle, by 65%, and 62%, respectively, without affecting systolic blood pressure, left ventricle/body weight, or cross-sectional area of myocardial fibers. Collagen deposition of coronary arteries was reduced by the AM infusion (-24%, p<0.01), and these effects of AM were accompanied by significant reductions in gene expression of type 1 collagen (-49%, p<0.05) and transforming growth factor-beta1 (TGF-beta1) (-55%, p<0.01). In cultured cardiac fibroblasts, 10(-7) mol/L AM exerted an inhibitory effect on TGF-beta1-induced alpha-SMA expression (p<0.01) that was mimicked by 8-bromo-cAMP and attenuated by the protein kinase A inhibitor H-89.


CONCLUSIONS
AM decreased Ang II-induced collagen deposition surrounding the coronary arteries, inhibiting myofibroblast differentiation and expressions of ECM-related genes in rats. The present findings further support the biological action of AM as an antifibrotic factor in vascular remodeling.
Tsuruda
Toshihiro
T
First Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, 5200 Kihara Kiyotake, Miyazaki 889-1692, Japan. ttsuruda@med.miyazaki-u.ac.jp
Kato
Johji
J
Hatakeyama
Kinta
K
Masuyama
Hiroyuki
H
Cao
Yuan-Ning
YN
Imamura
Takuroh
T
Kitamura
Kazuo
K
Asada
Yujiro
Y
Eto
Tanenao
T
D000199:Actins / Q000378:metabolism; D053607:Adrenomedullin; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000097:blood / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003238:Connective Tissue / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D010455:Peptides / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D020257:Ventricular Remodeling / Q000187:drug effects
D000199:Actins; D002316:Cardiotonic Agents; D024042:Collagen Type I; D010455:Peptides; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D053607:Adrenomedullin