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 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-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 (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.
Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
U
U
Schönbeck
F
F
Mach
G K
GK
Sukhova
E
E
Atkinson
E
E
Levesque
M
M
Herman
P
P
Graber
P
P
Basset
P
P
Libby
D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand; D002339:Carotid Arteries / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D053507:Matrix Metalloproteinase 11; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000302:isolation & purification; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D015398:Signal Transduction
D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D011973:Receptors, LDL; D023201:CD40 Ligand; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases