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Journal of Lipid Research, Vol. 48, 768-781, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis

Masako Tabuchi^*, Katsumi Inoue^,, Hitomi Usui-Kataoka^**, Kazuko Kobayashi^*, Misako Teramoto, Koji Takasugi^**, Kenichi Shikata^**, Masahiro Yamamura^**, Kenji Ando, Keiichiro Nishida, Junko Kasahara^***, Noriaki Kume, Luis R. Lopez, Kazuaki Mitsudo, Masakiyo Nobuyoshi, Tatsuji Yasuda^*, Toru Kita, Hirofumi Makino^** and Eiji Matsuura^1,*

^* Department of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
^** Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
Department of Pathology, Kokura Memorial Hospital, Kitakyushu 802-8555, Japan
Department of Cardiology, Kokura Memorial Hospital, Kitakyushu 802-8555, Japan
Department of Cardiovascular Medicine, Kurashiki Central Hospital, Kurashiki 710-8602, Japan
^*** Department of Internal Medicine, Okayama Central Hospital, Okayama 700-0017, Japan
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
Corgenix, Inc., Broomfield, CO 80020

Published, JLR Papers in Press, January 29, 2007.

¹ To whom correspondence should be addressed. e-mail: eijimatu{at}md.okayama-u.ac.jp

C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with ß2-glycoprotein I (ß2GPI), implicating oxLDL/ß2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/ß2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/ß2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and ß2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of atherosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/ß2GPI complexes correlated with total cholesterol and hemoglobin A1c. Thus, the generation of CRP/oxLDL/ß2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/ß2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis.

Supplementary key words ß2-glycoprotein I • oxidized LDL/ß2-glycoprotein I complexes • diabetes mellitus • oxidized LDL

Abbreviations: APS, antiphospholipid syndrome; AT, atherosclerosis; CRP, C-reactive protein; CVD, cardiovascular disease; DM, diabetes mellitus; ß2GPI, ß2-glycoprotein I; HbA1c, hemoglobin A1c; hsCRP, high-sensitivity CRP; ICAM-1, intercellular adhesion molecule-1; IMT, intima media thickness; MAb, monoclonal antibody; oxLDL, oxidized LDL; pI, isoelectric point; RA, rheumatoid arthritis; ROC, receiver operating characteristic; T-chol, total cholesterol; VCAM-1, vascular cell adhesion molecule-1

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