Inward remodeling of the rabbit aorta is blocked by the matrix metalloproteinase inhibitor doxycycline.
Constrictive arterial remodeling accounts for a significant proportion of lumen loss in atherosclerotic progression and postangioplasty stenosis. Recent research suggests that constrictive remodeling is mediated by turnover of the extracellular matrix. We hypothesized that remodeling could be attenuated by treatment with the safe, effective matrix metalloproteinase (MMP) inhibitor doxycycline. Female rabbit abdominal aortas were denuded using a 4-Fr balloon embolectomy catheter, and reinjured 3 weeks later. Treatment with 30 mg/kg/day doxycycline was begun the day before the second injury. At 6 weeks after injury, lumen area measured 13.1 +/- 1.2 mm(2) in controls compared to 17.5 +/- 1.6 mm(2) in doxycycline-treated rabbits (p = 0.05). At 4 days after injury, MMP-2 activity was increased compared to uninjured controls, but doxycycline treatment reduced MMP-2 activity. Doxycycline treatment also inhibited fibrillar collagen deposition in the intima by 87% as detected by polarized light microscopy. Doxycycline was an effective inhibitor of constrictive arterial remodeling in the rabbit aorta. Treatment reduced MMP activity and attenuated the deposition of extracellular matrix particularly in the intima.
Terrence Donnelly Cardiovascular Research Laboratories, St. Michael's Hospital, Toronto, Ontario, Canada.
David W
DW
Courtman
Christopher D
CD
Franco
Qinghe
Q
Meng
Michelle P
MP
Bendeck
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001012:Aorta, Abdominal / Q000201:enzymology / Q000293:injuries* / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D003094:Collagen / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology*; D004549:Elastin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D011817:Rabbits; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D005337:Fibrin; D003094:Collagen; D004549:Elastin; D004318:Doxycycline