Stromelysin-3 is an unusual matrix metalloproteinase, being released in the active rather than zymogen form and having a distinct substrate specificity, targeting serine proteinase inhibitors (serpins), which regulate cellular functions involved in atherosclerosis. We report here that human atherosclerotic plaques (n = 7) express stromelysin-3 in situ, whereas fatty streaks (n = 5) and normal arterial specimens (n = 5) contain little or no stromelysin-3. Stromelysin-3 mRNA and protein colocalized with endothelial cells, smooth muscle cells, and macrophages within the lesion. In vitro, usual inducers of matrix metalloproteinases such as interleukin-1, interferon-γ, or tumor necrosis factor α did not augment stromelysin-3 in vascular wall cells. However, T cell–derived as well as recombinant CD40 ligand (CD40L, CD154), an inflammatory mediator recently localized in atheroma, induced de novo synthesis of stromelysin-3. In addition, stromelysin-3 mRNA and protein colocalized with CD40L and CD40 within atheroma. In accordance with the in situ and in vitro data obtained with human material, interruption of the CD40–CD40L signaling pathway in low density lipoprotein receptor–deficient hyperlipidemic mice substantially decreased expression of the enzyme within atherosclerotic plaques. These observations establish the expression of the unusual matrix metalloproteinase stromelysin-3 in human atherosclerotic lesions and implicate CD40–CD40L signaling in its regulation, thus providing a possible new pathway that triggers complications within atherosclerotic lesions.
Expression of Stromelysin-3 in Atherosclerotic Lesions: Regulation via CD40–CD40 Ligand Signaling In Vitro and In Vivo
Address correspondence to Peter Libby, Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave., LMRC 307, Boston, MA 02115. Phone: 617-732-6628; Fax: 617-732-6961; E-mail: [email protected]
Abbreviations used in this paper: α2-AP, α2-antiplasmin; α1-AT, α1-antitrypsin; α2-M, α2-macroglobulin; α1-PI, α1-proteinase inhibitor; AT-III, antithrombin III; EC, endothelial cells; FBS, fetal bovine serum; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; LDLR−/−, low density lipoprotein receptor deficient; MMP, matrix metalloproteinase; MØ, macrophages; PMA, Phorbol-12 myristate 13-acetate; RT, reverse transcription; SMC, smooth muscle cells.
Uwe Schönbeck, François Mach, Galina K. Sukhova, Elizabeth Atkinson, Ethan Levesque, Michael Herman, Pierre Graber, Paul Basset, Peter Libby; Expression of Stromelysin-3 in Atherosclerotic Lesions: Regulation via CD40–CD40 Ligand Signaling In Vitro and In Vivo . J Exp Med 1 March 1999; 189 (5): 843–853. doi: https://doi.org/10.1084/jem.189.5.843
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