Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme.

Abstract

Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme ( ABSTRACTCertain matrix metalloproteinases (MMP) are expressed within the fibrous areas surrounding acellular lipid cores of atherosclerotic plaques, suggesting that these proteinases degrade matrix proteins within these areas and weaken the structural integrity of the lesion. We report that matrilysin and macrophage metalloelastase, two broad-acting MMPs, were expressed in human atherosclerotic lesions in carotid endarterectomy samples (n = 18) but were not expressed in normal arteries (n = 7). In situ hybridization and immunohistochemistry revealed prominent expression of matrilysin in cells confined to the border between acellular lipid cores and overlying fibrous areas, a distribution distinct from other MMPs found in similar lesions. Metalloelastase was expressed in these same border areas. Matrilysin was present in lipid-laden macrophages, identified by staining with anti-CD-68 antibody. Furthermore, endarterectomy tissue in organ culture released matrilysin. Staining for versican demonstrated that this vascular proteoglycan was present at sites of matrilysin expression. Biochemical studies showed that matrilysin degraded versican much more efficiently than other MMPs present in atherosclerotic lesions. Our findings suggest that matrilysin, specifically expressed in atherosclerotic lesions, could cleave structural proteoglycans and other matrix components, potentially leading to separation of caps and shoulders from lipid cores.

Bone tissue engineering: A review in bone biomimetics and drug delivery strategies

“…Research indicates that these proteoglycans do influence cell behavior by blocking adhesion motifs from RGD-containing molecules and also binding TGF-b. 85 The last class of ECM proteins are glycoproteins. Glycoproteins are carbohydrates with distinct active domains and play key roles in cell signaling.…”

Control of matrix metalloproteinase catalytic activity

“…However, full activation of proMMP-7 requires both a molar excess of MMP-3 and an extended incubation, suggesting MMP-3 is not an efficient activator of MMP-7 (Imai et al, 1995). Furthermore, MMP-3 is not typically co-expressed with MMP-1 (Parks, 1999;Saarialho-Kere et al, 1994) nor with MMP-7 in vivo (Dunsmore et al, 1998;Halpert et al, 1996;Rudolph-Owen et al, 1997). Second, if co-localized, the putative activating MMP may not be present in sufficient relative amounts to cleave the zymogen, particularly in a pericellular microenvironment that contain high concentrations of other or authentic substrates.…”

“…Kinetic studies with model substrates have demonstrated that specific enzymes degrade some substrates more efficiently than others. For example, both MMP-2 and MMP-9 act on cleaved collagen better than other MMPs, (Mackay et al, 1990) and human MMP-7 is a more potent proteoglycanase and elastase than other MMPs (Filippov et al, 2003;Halpert et al, 1996). Thus, in a tissue environment, which contains many potential substrates, selectivity of MMP catalysis, in addition to being regulated by the concentration of active enzyme, may be directed by the concentration of a preferred substrate relative to that of other potential substrates within range of a secreted MMP.…”

Versican Degradation and Vascular Disease

“…For example, matrix metalloproteinase (MMP)-1 (Perides et al 1995), -2 (Passi et al 1999), -3 (Perides et al 1995, Halpert et al 1996), -7 (Halpert et al 1996, and -9 (Passi et al 1999) have been shown to degrade native, purified versican in vitro. Whereas MMP-8 cleaves aggrecan, the activity of this MMP against versican has not been studied.…”