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J. Biol. Chem., Vol. 280, Issue 50, 41521-41529, December 16, 2005

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S100A8 and S100A9 in Human Arterial Wall

IMPLICATIONS FOR ATHEROGENESIS^*

Michelle M. McCormick1, Farid Rahimi12, Yuri V. Bobryshev, Katharina Gaus, Hala Zreiqat, Hong Cai, Reginald S. A. Lord, and Carolyn L. Geczy3

From the School of Medical Sciences and the Surgical Professorial Unit, St. Vincent's Hospital, University of New South Wales, Sydney, New South Wales 2052, Australia

Atherogenesis is a complex process involving inflammation. S100A8 and S100A9, the Ca²⁺-binding neutrophil cytosolic proteins, are associated with innate immunity and regulate processes leading to leukocyte adhesion and transmigration. In neutrophils and monocytes the S100A8-S100A9 complex regulates phosphorylation, NADPH-oxidase activity, and fatty acid transport. The proteins have anti-microbial properties, and S100A8 may play a role in oxidant defense in inflammation. Murine S100A8 is regulated by inflammatory mediators and recruits macrophages with a proatherogenic phenotype. S100A9 but not S100A8 was found in macrophages in ApoE^-/- murine atherosclerotic lesions, whereas both proteins are expressed in human giant cell arteritis. Here we demonstrate S100A8 and S100A9 protein and mRNA in macrophages, foam cells, and neovessels in human atheroma. Monomeric and complexed forms were detected in plaque extracts. S100A9 was strongly expressed in calcifying areas and the surrounding extracellular matrix. Vascular matrix vesicles contain high levels of Ca²⁺-binding proteins and phospholipids that regulate calcification. Matrix vesicles characterized by electron microscopy, x-ray microanalysis, nucleoside triphosphate pyrophosphohydrolase assay and cholesterol/phospholipid analysis contained predominantly S100A9. We propose that S100A9 associated with lipid structures in matrix vesicles may influence phospholipid-Ca²⁺ binding properties to promote dystrophic calcification. S100A8 and S100A9 were more sensitive to hypochlorite oxidation than albumin or low density lipoprotein and immunoaffinity confirmed S100A8-S100A9 complexes; some were resistant to reduction, suggesting that hypochlorite may contribute to protein cross-linking. S100A8 and S100A9 in atherosclerotic plaque and calcifying matrix vesicles may significantly influence redox- and Ca²⁺-dependent processes during atherogenesis and its chronic complications, particularly dystrophic calcification.

Received for publication, August 26, 2005 , and in revised form, October 4, 2005.

^* This study was supported in part by a National Health and Research Council of Australia grant and by the St. Vincent's Clinic Foundation, Sydney. 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 Both authors contributed equally to this work.

² Recipient of an Australian Postgraduate Award. Present address: Prince of Wales Medical Research institute, Randwick NSW 2031, Australia.

³ To whom correspondence should be addressed: Inflammatory Diseases Research Unit, School of Medical Sciences, The University of New South Wales, Sydney NSW 2052, Australia. Tel.: 61-2-9385-2777; Fax: 61-2-9385-1389; E-mail: c.geczy{at}unsw.edu.au.

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