Metalloproteinases and their inhibitors are markers of plaque instability

BACKGROUND: Our aim was to investigate the release, activity, and expression of matrix metalloproteinases (MMPs)-1, -2, -3 and -9, and tissue inhibitors of metalloproteinases (TIMPs)-1 and -2 in patients undergoing carotid endarterectomy and to determine whether altered plasma levels of MMPs and TIMPs may be correlated with carotid instability. METHODS: The carotid plaques of 53 consecutive patients who underwent carotid endarterectomy were classified histologically as stable or unstable. The release of MMPs and TIMPs was analyzed in the serum of patients with stable and unstable carotid plaques, and in 15 age-matched healthy volunteers. The production, activity, and expression of MMPs and TIMPs were determined by Western blotting, zymography, and reverse transcriptase polymerase chain reaction in the carotid specimens. RESULTS: Twenty-nine (55%) patients had an unstable carotid plaque and 24 (45%) a stable plaque. Plasma levels of MMPs were higher in patients with unstable plaques compared to patients with stable plaques and healthy volunteers ( P < .001), whereas plasma levels of TIMPs were lower in patients with unstable plaques compared to patients with stable plaques and healthy volunteers ( P < .001). In the carotid specimens, we found increased activity, production, and expression of MMPs, and decreased activity, production and expression of TIMPs in unstable plaques compared to stable plaques ( P < .001). After endarterectomy, plasma levels of MMPs and TIMPs in patients with unstable and stable plaques returned to the values found in healthy volunteers. CONCLUSIONS: Our study demonstrated that an imbalance exists between MMPs and TIMPs in unstable carotid plaques, which is reflected in the plasma levels of these markers. These data may help in selecting patients at high risk for cerebral events.