J. Exp. Med., Volume 189, Number 5, March 1, 1999 843-853

Expression of Stromelysin-3 in Atherosclerotic Lesions: Regulation via CD40-CD40 Ligand Signaling In Vitro and In Vivo

By Uwe Schönbeck,^* François Mach,^* Galina K. Sukhova,^* Elizabeth Atkinson,^* Ethan Levesque,^* Michael Herman,^* Pierre Graber, Paul Basset,^§ and Peter Libby^*

From the ^* Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115;  Ares Serono, 1228 Geneva, Switzerland; and the ^§ Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, BP163, 67404 Illkirch cedex, France

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-, or tumor necrosis factor  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.

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