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Pleiotropic Roles of S100A12 in Coronary Atherosclerotic Plaque Formation and Rupture¹

Jesse Goyette^*, Wei Xing Yan^*, Eric Yamen, Yuen Ming Chung^*, Su Yin Lim^*, Kenneth Hsu^*, Farid Rahimi^*, Nick Di Girolamo^*, Changjie Song, Wendy Jessup, Maaike Kockx, Yuri V. Bobryshev^*, S. Ben Freedman and Carolyn L. Geczy^2,*

^* Centre for Infection and Inflammation Research, School of Medical Sciences, University of New South Wales, Sydney, Australia; ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, Australia; and Centre for Vascular Research, University of New South Wales, Sydney, Australia

Macrophages, cytokines, and matrix metalloproteinases (MMP) play important roles in atherogenesis. The Ca²⁺-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 Zn²⁺, we studied some functional aspects that could modulate atherogenesis. S100A12 formed a hexamer in the presence of Zn²⁺; a novel Ab was generated that specifically recognized this complex. By chelating Zn²⁺, S100A12 significantly inhibited MMP-2, MMP-9, and MMP-3, and the Zn²⁺-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 Zn²⁺.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was funded by the National Health and Medical Research Council of Australia.

² Address correspondence and reprint requests to Dr. Carolyn Geczy, School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia. E-mail address: c.geczy{at}unsw.edu.au

³ Abbreviations used in this paper: RAGE, receptor for advanced glycation end-products; EC, endothelial cell; ACS, acute coronary syndrome; anti-hexS100A12, anti-S100A12 hexamer; Ao, aortic root; APMA, 4-aminophenylmercuric acetate; BS³, bis(sulfosuccinimidyl)suberate; CAD, coronary artery disease; CRP, C-reactive protein; CS, coronary sinus; EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; ECM, extracellular matrix; FC, foam cells; MMP, matrix metalloproteinase; PCI, percutaneous coronary intervention; SA, stable angina pectoris; sRAGE, soluble receptor for advanced glycation end-products; STEMI, ST elevation myocardial infarction; TIMP, tissue inhibitors of metalloproteinase; vitamin D₃, 1,25-dihydroxycholecalciferol; BCS, bovine calf serum; HMDM, human monocyte-derived macrophages.