Expression of stromelysin-3 in atherosclerotic lesions: Regulation via CD40-CD40 ligand signaling in vitro and in vivo

Stromelysin-3 is an unusual matrix metalloproteinase, being released in the active rather than zymogen form and having a distinct substrate specificit y, targeting serine proteinase inhibitors (serpins), which regulate cellula r functions involved in atherosclerosis. We report here that human atherosc lerotic plaques (n = 7) express stromelysin-3 in situ, whereas fatty streak s (n = 5) and normal arterial specimens (n = 5) contain little or no strome lysin-3. Stromelysin-3 mRNA and protein colocalized with endothelial cells, smooth muscle cells, and macrophages within the lesion. In vitro, usual in ducers of matrix metalloproteinases such as interleukin-1, interferon-gamma , or tumor necrosis factor alpha did not augment stromelysin-3 in vascular wall cells. However, T cell-derived as well as recombinant CD40 ligand (CD4 0L, CD154), an inflammatory mediator recently localized in atheroma, induce d de novo synthesis of stromelysin-3. In addition, stromelysin-3 mRNA and p rotein 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-defic ient hyperlipidemic mice substantially decreased expression of the enzyme w ithin atherosclerotic plaques. These observations establish the expression of the unusual matrix metalloproteinase stromelysin-3 in human atherosclero tic lesions and implicate CD40-CD40L signaling in its regulation, thus prov iding a possible new pathway that triggers complications within atheroscler otic lesions.