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J. Biol. Chem., Vol. 282, Issue 32, 23698-23707, August 10, 2007

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Differential Association of Hemoglobin with Proinflammatory High Density Lipoproteins in Atherogenic/Hyperlipidemic Mice

A NOVEL BIOMARKER OF ATHEROSCLEROSIS^*

Junji Watanabe, Katherine J. Chou^¶, James C. Liao^¶, Yunan Miao^||, Hsiang-Hui Meng^||, Helen Ge^||, Victor Grijalva, Susan Hama, Kathy Kozak^**, Georgette Buga, Julian P. Whitelegge, Terry D. Lee^||, Robin Farias-Eisner^**, Mohamad Navab¹, Alan M. Fogelman¹², and Srinivasa T. Reddy¹³

From the Atherosclerosis Research Unit, Department of Medicine/Cardiology, Department of Molecular and Medical Pharmacology, ^¶Department of Chemical and Bimolecular Engineering, ^**Department of Obstetrics and Gynecology, The Semel Institute for Neuroscience and Human Behavior, and Molecular Biology Institute, University of California, Los Angeles, California 90095 and ^||Division of Immunology, Beckman Research Institute, City of Hope, Duarte, California 91010

Studies in both mice and humans suggest that the anti- or proinflammatory nature of high density lipoprotein (HDL) may be a more sensitive predictor of risk for coronary heart disease events. In this study, we report the identification and characterization of two proteins (m/z 14,900 and 15,600) that are most dramatically associated with HDL in mouse models of atherosclerosis. Mass spectral analyses of proinflammatory HDL identified the two peaks to be hemoglobin (Hb) and chains, respectively, with no apparent post-translational modification. Biochemical analysis confirmed the differential association of Hb with HDL from hyperlipidemic mice. We further show that HDL-associated Hb is predominantly in the oxyHb form with distinct physical and chemical properties. Furthermore oxyHb-containing proinflammatory HDL potently consumed nitric oxide and contracted arterial vessels ex vivo. Moreover Hb also was found differentially associated with HDL from coronary heart disease patients compared with healthy controls. Our data suggest that Hb contributes to the proinflammatory nature of HDL in mouse and human models of atherosclerosis and may serve as a novel biomarker for atherosclerosis.

Received for publication, March 13, 2007 , and in revised form, May 15, 2007.

^* This work was supported by NHLBI, National Institutes of Health Grants 1RO1HL71776 (to S. T. R.) and HL-30568 (to A. M. F., M. N., and S. T. R.) and the Laubisch, Castera, and M. K. Grey Funds at UCLA. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. 1-5.

¹ Principals in Bruin Pharma.

² An officer in Bruin Pharma.

³ To whom correspondence should be addressed: Dept. of Medicine/Cardiology, Dept. of Molecular and Medical Pharmacology, University of California Los Angeles, 650 Charles E. Young Dr. S., A8-131, CHS, Los Angeles, CA 90095. Tel.: 310-206-3915; Fax: 310-206-3605; E-mail: sreddy{at}mednet.ucla.edu.

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