Prospective, randomized, double-blind trial investigating the effect of doxycycline on matrix metalloproteinase expression within atherosclerotic carotid plaques.
OBJECTIVE
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 micro 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 (P=0.038). This difference was due to decreased MMP-1 transcript (P<0.001). 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.
Axisa
Benedict
B
Department of Surgery, University of Leicester, Leicester, UK.
Loftus
Ian M
IM
Naylor
A Ross
AR
Goodall
Steven
S
Jones
Louise
L
Bell
Peter R F
PR
Thompson
Matthew M
MM
D000368:Aged; D001161:Arteriosclerosis / Q000201:enzymology / Q000473:pathology; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D004311:Double-Blind Method; D004318:Doxycycline / Q000032:analysis / Q000627:therapeutic use*; D016894:Endarterectomy, Carotid; D004790:Enzyme Induction / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000032:analysis / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1; D004318:Doxycycline