Prospective, Randomized, Double-Blind Trial Investigating the Effect of Doxycycline on Matrix Metalloproteinase Expression Within Atherosclerotic Carotid Plaques

Abstract

Background and Purpose-Elevated levels of matrix metalloproteinases (MMPs), particularly MMP-1 and MMP-9, have been implicated in plaque rupture. It has been suggested that inhibition of MMPs may stabilize vulnerable atherosclerotic plaques and improve clinical outcome. The aim of the study was to investigate the ability of doxycycline, a nonspecific MMP inhibitor, to reduce MMP concentration in carotid atheroma. Methods-The study design was a prospective, double-blind randomized trial. One hundred patients requiring carotid endarterectomy were randomized to receive 200 mg/d doxycycline or placebo for 2 to 8 weeks before surgery. During endarterectomy, carotid plaques were retrieved. The concentrations of MMPs and doxycycline were determined in the atherosclerotic tissue by enzyme-linked immunosorbent assay and high-performance liquid chromatography, respectively. Clinical events were recorded, as was the rate of preoperative embolization (transcranial Doppler). Results-Analysis of endarterectomized specimens demonstrated a mean doxycycline concentration of 6.0 g/g wet weight in treated patients. Administration of doxycycline significantly reduced the concentration of MMP-1 in carotid plaques from a mean of 14.8 to 10.3 ng/100g wet weight (Pϭ0.038). This difference was due to decreased MMP-1 transcript (PϽ0.001). There was no difference in any other MMP (MMP-2, -3, or -9) or tissue inhibitor of matrix metalloproteinases-1 or -2. Conclusions-Doxycycline penetrated atherosclerotic plaques with acceptable tissue levels. This resulted in a reduction in MMP-1 concentration because of decreased expression.

Suppression of MMP-9 by Doxycycline in Brain Arteriovenous Malformations

“…In patients with abdominal aortic aneurysm, doxycycline treatment for one week prior to the repair surgery resulted in decreased MMP-9 and MMP-2 in the wall of the aneurysms [10]. Similar results have been reported in patients with atherosclerotic carotid plaques who received doxycycline for 2-8 weeks [11].…”

“…Accordingly, a sample size of 46 in each group would be needed to demonstrate a difference in active MMP-9, assuming an alpha of 0.05 and power of 80%. However, variance may be reduced by utilizing a longer duration of treatment, as suggested by studies in other diseases [11,12]. A clinical study with a modestly larger sample size and longer treatment duration should suffice to verify effects of oral doxycycline on reducing MMP-9 activity in AVMs.…”

Clinical and Biochemical Results of the Metalloproteinase Inhibition with Subantimicrobial Doses of Doxycycline to Prevent Acute Coronary Syndromes (MIDAS) Pilot Trial

“…22 Although the mechanism of this reduction in risk is unknown, the tetracycline family of antibiotics, including SDD, is capable of entering the arterial wall, 23 where it may inhibit cytokine and protease mediators of several inflammatory cascades that may contribute to plaque instability. 4 Tetracycline has been shown to block endotoxin-induced secretion of tumor necrosis factor and IL-1 in cultured monocytes, 24 downregulate the expression and activity of MMP-2 and MMP-9, 25 and inhibit IL-6 expression.…”

The Matrix Metalloproteinases and Cerebral Ischemia

“…MMP-9 is mainly affected by the regulation of plasminogen activator and its subsrates inclucde gelatinase, collagen types IV, V and elastin [2] . Researches have shown that MMP-2 and MMP-9 may play a role in angiogenesis [3] , atherosclerosis [4,5] and ischemic brain injury [6] .…”

“…Studies also show that MMP-2 is related to the regeneration of axons. A growing number of scholars believe that MMPs plays an important role in the pathologic processes of central nervous system diseases [5] .…”