Circulation. 2001;104:1899-1904
doi: 10.1161/hc4101.097419
doi: 10.1161/hc4101.097419
(Circulation. 2001;104:1899.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Expression of Neutrophil Collagenase (Matrix Metalloproteinase-8) in Human Atheroma
A Novel Collagenolytic Pathway Suggested by Transcriptional Profiling
From The Leducq Center for Cardiovascular Research (M.P.H., G.K.S., P.L., N.G., D.B.H., M.K., U.S.), Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass, and Millennium Pharmaceuticals, Inc (N.T., R.E.B., M.C.), Cambridge, Mass.
Correspondence to Uwe Schöbeck, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 309, Boston, MA 02115. E-mail uschoenbeck{at}rics.bwh.harvard.edu
Background— Loss of interstitial collagen, particularly type I collagen, the major load-bearing molecule of atherosclerotic plaques, renders atheroma prone to rupture. Initiation of collagen breakdown requires interstitial collagenases, a matrix metalloproteinase (MMP) subfamily consisting of MMP-1, MMP-8, and MMP-13. Previous work demonstrated the overexpression of MMP-1 and MMP-13 in human atheroma. However, no study has yet evaluated the expression of MMP-8, known as "neutrophil collagenase," the enzyme that preferentially degrades type I collagen, because granulocytes do not localize in plaques.
Methods and Results— Transcriptional profiling and reverse transcription–polymerase chain reaction analysis revealed inducible expression of MMP-8 transcripts in CD40 ligand–stimulated mononuclear phagocytes. Western blot analysis demonstrated that 3 atheroma-associated cell types, namely, endothelial cells, smooth muscle cells, and mononuclear phagocytes, expressed MMP-8 in vitro upon stimulation with proinflammatory cytokines such as interleukin-1ß, tumor necrosis factor-
, or CD40 ligand. MMP-8 protein elaborated from these atheroma-associated cell types migrated as 2 immunoreactive bands, corresponding to the molecular weights of the zymogen and the active molecule. Extracts from atherosclerotic, but not nondiseased arterial tissue, contained similar immunoreactive bands. Moreover, all 3 cell types expressed MMP-8 mRNA and protein in human atheroma in situ. Notably, MMP-8 colocalized with cleaved but not intact type I collagen within the shoulder region of the plaque, a frequent site of rupture.
Conclusions— These data point to MMP-8 as a previously unsuspected participant in collagen breakdown, an important determinant of the vulnerability of human atheroma.
Key Words: atherosclerosis • collagen • metalloproteinases • inflammation
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