Do metalloproteinases destabilize vulnerable atherosclerotic plaques?
OBJECTIVE
Atherosclerotic plaque rupture and thrombosis underlie most myocardial infarctions. Matrix metalloproteinases are a family of enzymes that remodel the extracellular matrix. Metalloproteinases could stabilize rupture-prone plaques by promoting smooth muscle cell migration and proliferation. Alternatively, metalloproteinases could destabilize vulnerable plaques by promoting matrix destruction, angiogenesis, leucocyte infiltration, and apoptosis. Evidence is reviewed from genetically modified mice and human biomarker and genetic studies that sheds light on this dual role of metalloproteinases.


RESULTS
Inhibition of metalloproteinases in mice using tissue inhibitors of metalloproteinases increases plaque stability; however, double knockouts of apolipoprotein E with matrix metalloproteinase 2, 3, 7, 9, 12, and 13 have more or less stable plaques, consistent with harmful or protective effects of individual metalloproteinases. Overexpression studies in mice or rabbits show that high activities of matrix metalloproteinase 9 and 12 decrease stability. Biomarker and human genetic studies demonstrate that increased metalloproteinase activity is associated with vascular repair or myocardial infarction.


CONCLUSIONS
Recent studies reinforce evidence for a dual role of matrix metalloproteinases in plaque stabilization and rupture, which probably depends on the stage, site, and severity of disease. Dysregulated metalloproteinase activity in end-stage coronary artery disease appears a valid target for therapy.
Newby
Andrew C
AC
Bristol Heart Institute, Royal Infirmary, University of Bristol, Bristol BS2 8HW, UK. A.Newby@bris.ac.uk
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011480:Protease Inhibitors / Q000627:therapeutic use
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases