title: Enhanced expression of vascular matrix metalloproteinases induced in vitro by cytokines and in regions of human atherosclerotic lesions.
abstract: Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during atherogenesis. The ability of vascular cells to synthesize the components of ECM is well characterized, but less is known about their capacity to degrade ECM and the factors that may regulate this process. We therefore studied the expression of matrix metalloproteinases (MMPs), enzymes that degrade various components of ECM, and of tissue inhibitors of MMPs (TIMPs) by untreated or cytokine-stimulated human smooth muscle cells (SMC). Messenger RNA was studied by Northern blotting, and proteins secreted in culture by SMC were identified by immunoprecipitation. Gelatinolytic and caseinolytic activity of MMPs was detected zymographically. SMC constitutively produced a 72 kDa type IV gelatinase (GL), TIMP-1, and TIMP-2. Upon stimulation with IL1 or TNF alpha, SMC synthesized in addition 92 kDa GL, stromelysin, and interstitial collagenase, MMPs that together can degrade all of the ECM components. IL1 or TNF alpha did not alter the level of TIMP mRNA and protein, suggesting that a net excess of MMP production under these conditions may promote breakdown of the vascular ECM. To test the in vivo relevance of these in vitro findings, we analyzed immunohistochemically normal human arteries and carotid atheromas. Normal tissue and the medial layer underlying lesions stained uniformly for 72 kDa GL and TIMPs 1 and 2. Lesions showed regionally increased MMP expression: the shoulders of atherosclerotic plaques contained stromelysin and 92 kDa GL associated with SMC, and clusters of macrophage-derived foam cells associated with the lipid core stained intensely for all MMPs studied. Endothelial cells covering atheroma or of the plaque microvasculature contained interstitial collagenase. In pathological conditions associated with local release of cytokines in the vessel wall, enhanced regional expression of vascular MMPs may contribute to SMC migration and weakening of matrix that would favor plaque rupture, events associated with the development or complication of the atherosclerotic lesions.
authors.affiliation: Brigham and Women's Hospital, Boston, Massachussetts, USA.
authors.forename: Z S
authors.initials: ZS
authors.lastname: Galis
authors.forename: M
authors.initials: M
authors.lastname: Muszynski
authors.forename: G K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: E
authors.initials: E
authors.lastname: Simon-Morrissey
authors.forename: P
authors.initials: P
authors.lastname: Libby
mesh_terms: D001158:Arteries / Q000201:enzymology; D001161:Arteriosclerosis / Q000201:enzymology*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D006023:Glycoproteins; D007375:Interleukin-1; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D018093:Gelatinases; D008666:Metalloendopeptidases