Distribution profiles of membrane Type-1 matrix metalloproteinase (MT1-MMP), matrix metalloproteinase-2 (MMP-2) and cyclooxygenase-2 (COX-2) in rabbit atherosclerosis: comparison with plaque instability analysis.
BACKGROUND
Despite increasing evidence that membrane type 1 matrix metalloproteinase (MT1-MMP), matrix metalloproteinase-2 (MMP-2), and cyclooxygenase-2 (COX-2) are involved in the pathogenesis of atherosclerosis, the possible links among these enzymes remain unclear. Accordingly, we investigated the distribution of MT1-MMP, MMP-2, and COX-2 immunohistologically in the atherosclerotic lesions of hypercholesterolemic (WHHLMI) rabbits.


RESULTS
Distribution of MT1-MMP, MMP-2, and COX-2 was examined by immunohistochemical staining using sixty cross sections of the ascending-arch and thoracic aortas prepared from 4 WHHLMI rabbits. MT1-MMP and MMP-2 staining was prominently observed in the macrophage-rich regions of the atheromatous lesions, and was positively correlated with morphological vulnerability (r=0.63 for MT1-MMP; r=0.60 for MMP-2; p<0.0001). MT1-MMP staining was positively correlated with MMP-2 staining (r=0.61, p<0.0001). COX-2 staining was also the highest in the macrophage-rich regions of the atheromatous lesions, with relatively high staining levels in other more stable lesions.


CONCLUSIONS
Co-distribution of MT1-MMP, MMP-2, and COX-2 was demonstrated in grade IV atheroma, indicating a possible link among these enzymes in the destabilization of atherosclerotic plaques. The relatively high COX-2 distribution in other more stable lesions may indicate its additional roles in the stabilization of atherosclerotic lesions. The present findings in hypercholesterolemic rabbits should help advance our understanding of the pathophysiology of atherosclerosis and provide useful information for the development of new therapeutic and diagnostic (imaging) agents that target MMPs and COX-2 in atherosclerosis.
Kuge
Yuji
Y
Department of Patho-functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. kuge@pharm.kyoto-u.ac.jp
Takai
Nozomi
N
Ishino
Seigo
S
Temma
Takashi
T
Shiomi
Masashi
M
Saji
Hideo
H
D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000473:pathology; D050197:Atherosclerosis / Q000145:classification / Q000201:enzymology* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D011817:Rabbits