Copyright © 2004, European Society of Cardiology
Antifibrotic effect of adrenomedullin on coronary adventitia in angiotensin II-induced hypertensive rats
aFirst Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, 5200 Kihara Kiyotake, Miyazaki 889-1692, Japan
bDepartment of Nutrition Management, Faculty of Health and Nutrition, Minami-Kyushu University, Japan
cFirst Department of Pathology, Miyazaki Medical College, University of Miyazaki, Japan
* Corresponding author. First Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, 5200 Kihara Kiyotake, Miyazaki 889-1692, Japan. Tel.: +81 985 85 0872; fax: +81 985 85 6596. Email address: ttsuruda{at}med.miyazaki-u.ac.jp
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.
Methods and results: Rats with hypertension induced by Ang II infusion were administered 0.06 µg/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 
-smooth muscle actin (-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-β1 (TGF-β1) (–55%, p<0.01). In cultured cardiac fibroblasts, 10–7 mol/L AM exerted an inhibitory effect on TGF-β1-induced -SMA expression (p<0.01) that was mimicked by 8-bromo-cAMP and attenuated by the protein kinase A inhibitor H-89.
Conclusion: 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.
KEYWORDS Extracellular matrix; Fibrosis; Hypertension; Peptide hormone; Remodeling
Time for primary review 26 days
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