Pleiotropic roles of S100A12 in coronary atherosclerotic plaque formation and rupture.
Macrophages, cytokines, and matrix metalloproteinases (MMP) play important roles in atherogenesis. The Ca(2+)-binding protein S100A12 regulates monocyte migration and may contribute to atherosclerosis by inducing proinflammatory cytokines in macrophages. We found significantly higher S100A12 levels in sera from patients with coronary artery disease than controls and levels correlated positively with C-reactive protein. S100A12 was released into the coronary circulation from ruptured plaque in acute coronary syndrome, and after mechanical disruption by percutaneous coronary intervention in stable coronary artery disease. In contrast to earlier studies, S100A12 did not stimulate proinflammatory cytokine production by human monocytes or macrophages. Similarly, no induction of MMP genes was found in macrophages stimulated with S100A12. Because S100A12 binds Zn(2+), we studied some functional aspects that could modulate atherogenesis. S100A12 formed a hexamer in the presence of Zn(2+); a novel Ab was generated that specifically recognized this complex. By chelating Zn(2+), S100A12 significantly inhibited MMP-2, MMP-9, and MMP-3, and the Zn(2+)-induced S100A12 complex colocalized with these in foam cells in human atheroma. S100A12 may represent a new marker of this disease and may protect advanced atherosclerotic lesions from rupture by inhibiting excessive MMP-2 and MMP-9 activities by sequestering Zn(2+).
Goyette
Jesse
J
Centre for Infection and Inflammation Research, University of New South Wales, Sydney, Australia.
Yan
Wei Xing
WX
Yamen
Eric
E
Chung
Yuen Ming
YM
Lim
Su Yin
SY
Hsu
Kenneth
K
Rahimi
Farid
F
Di Girolamo
Nick
N
Song
Changjie
C
Jessup
Wendy
W
Kockx
Maaike
M
Bobryshev
Yuri V
YV
Freedman
S Ben
SB
Geczy
Carolyn L
CL
D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003327:Coronary Disease / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000502:physiology; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D012422:Rupture, Spontaneous / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control; D009418:S100 Proteins / Q000097:blood / Q000502:physiology*; D000067616:S100A12 Protein; D015032:Zinc / Q000502:physiology
D015415:Biomarkers; D018836:Inflammation Mediators; D061965:Matrix Metalloproteinase Inhibitors; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D015032:Zinc