Doxycycline attenuates isoproterenol-induced myocardial fibrosis and matrix metalloproteinase activity in rats.
Our objective was to investigate the effects of doxycycline, a matrix metalloproteinase (MMP) inhibitor (MMPi) on beta-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 beta-agonist signaling pathway, and that MMP-inhibiting compounds may attenuate myocardial fibrosis.
Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034-8628, Japan. hori@vmas.kitasato-u.ac.jp
Yasutomo
Y
Hori
Shoh-ichi
S
Kunihiro
Shingo
S
Sato
Kazuki
K
Yoshioka
Yukio
Y
Hara
Kazutaka
K
Kanai
Fumio
F
Hoshi
Naoyuki
N
Itoh
Seiichi
S
Higuchi
D000318:Adrenergic beta-Agonists; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use*; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar
D000318:Adrenergic beta-Agonists; D000900:Anti-Bacterial Agents; D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007545:Isoproterenol; D004318:Doxycycline