Doxycycline Attenuates Isoproterenol-Induced Myocardial Fibrosis and Matrix Metalloproteinase Activity in Rats

• Published in: Biological & Pharmaceutical Bulletin Vol. 32; no. 10; pp. 1678 - 1682
• Main Authors: Hori, Yasutomo, Kunihiro, Shoh-ichi, Sato, Shingo, Yoshioka, Kazuki, Hara, Yukio, Kanai, Kazutaka, Hoshi, Fumio, Itoh, Naoyuki, Higuchi, Seiichi
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 01.10.2009; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Adrenergic beta-Agonists; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; doxycycline; Doxycycline - pharmacology; Doxycycline - therapeutic use; fibrosis; Fibrosis - chemically induced; Fibrosis - drug therapy; Heart - drug effects; Isoproterenol; matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors; Myocardium - metabolism; Myocardium - pathology; Rats; Rats, Wistar
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.32.1678

Our objective was to investigate the effects of doxycycline, a matrix metalloproteinase (MMP) inhibitor (MMPi) on β-agonist-induced myocardial fibrosis and MMP expression. Twenly-four Wistar-Kyoto rats were divided into 3 groups: control (CTL; n=8), isoproterenol (ISO; n=8), and isoproterenol with doxycycline (ISO+DOX; n=8). ISO and ISO+DOX rats received L-isoproterenol (2.0 mg/kg/d) for 14 d, whereas the CTL group received vehicle. In addition, ISO+DOX rats received a subcutaneous injection of doxycycline (25 mg/kg/d) for 14 d, whereas CTL and ISO rats were injected with saline. Cardiac fibrosis was evaluated via histopathological analysis. MMP-2 and -9 were analyzed by Western blotting and zymography. Compared to the control, the myocardial cross-sectional area and areas of fibrosis were increased significantly in the ISO group, but were attenuated in the ISO+DOX group. MMP-2 activity also increased significantly in the ISO group, but decreased in the ISO+DOX group. Similarly, immunoblotting showed significant increase in MMP-2 and -9 levels in the ISO group, and decreased levels in the ISO+DOX group. Our results suggest that the enhanced expression of MMPs plays a prominent role in promoting myocardial fibrosis in β-agonist signaling pathway, and that MMP-inhibiting compounds may attenuate myocardial fibrosis.