Matrix metalloproteinase hypothesis of plaque rupture: players keep piling up but questions remain.

Arterial thrombosis is generally recognized as the proximate event responsible for most acute ischemic syndromes resulting from atherosclerotic vascular disease.1,2 The majority of such thrombi (60% to 80%) occur at sites of fissure or rupture of a thinned fibrous cap overlying a lipid-rich atherosclerotic lesion with intimal and adventitial inflammation, and the remainder occur over areas of superficial plaque erosion.1–5 The severity of luminal stenosis produced by such lesions before plaque rupture is frequently only mild or moderate, although the plaques tend to be large, and this seeming paradox is mostly because of the outward remodeling of the vessel wall.1,6,7 See p 1899 The precise mechanism(s) responsible for plaque rupture remain to be defined; however, the excessive degradation of the extracellular matrix scaffold has been implicated as one of the major molecular mechanisms in this process. A likely culprit is a family of matrix-degrading metalloproteinases (MMPs) expressed in human atherosclerotic lesions around the lipid core; they generally colocalize with macrophages/foam cells and, to a lesser extent, with smooth muscle cells and endothelial cells.8–11 Further suggesting a role for macrophage MMPs is their association with evidence of collagen breakdown in vitro and in vivo.9,12,13 Increased MMP expression in the cells resident in atherosclerotic plaques has been attributed to lipid ingestion, stimulation by oxidized LDL, cytokines, hemodynamic stress, ligation of CD-40, infection, and increased expression of Tenascin-c.14–21 The MMP family of enzymes includes collagenases (MMP-1 or interstitial collagenase, MMP-8 or neutrophil collagenase, and MMP-13 or collagenase 3), gelatinases (MMP-2 or gelatinase A and MMP-9 or gelatinase B), stromelysins (MMP-3, MMP-10, and MMP-11), membrane-bound MMPs (MT-MMPs 1 through 4) matrilysin (MMP-7), and metalloelastase (MMP-12). In the present issue of Circulation , Herman et al22 report that MMP-8, also known as the neutrophil collagenase, is also expressed …