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J. Biol. Chem., Vol. 280, Issue 1, 38-47, January 7, 2005
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Localization of Nitration and Chlorination Sites on Apolipoprotein A-I Catalyzed by Myeloperoxidase in Human Atheroma and Associated Oxidative Impairment in ABCA1-dependent Cholesterol Efflux from Macrophages*
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From the
Departments of Cell Biology and ¶Cardiovascular Medicine and the ||Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, Ohio 44195, the Department of Chemistry, Cleveland State University, Cleveland, Ohio 44115, the **Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
We recently reported that apolipoprotein A-I (apoA-I), the major protein component of high density lipoprotein, is a selective target for myeloperoxidase (MPO)-catalyzed nitration and chlorination in both and serum of subjects with cardiovascular disease. We further showed that the extent of both apoA-I nitration and chlorination correlated with functional impairment in reverse cholesterol transport activity of the isolated lipoprotein. Herein we used tandem mass spectrometry to map the sites of MPO-mediated apoA-I nitration and chlorination in vitro and in vivo and to relate the degree of site-specific modifications to loss of apoA-I lipid binding and cholesterol efflux functions. Of the seven tyrosine residues in apoA-I, Tyr-192, Tyr-166, Tyr-236, and Tyr-29 were nitrated and chlorinated in MPO-mediated reactions. Site-specific liquid chromatography-mass spectrometry quantitative analyses demonstrated that the favored modification site following exposure to MPO-generated oxidants is Tyr-192. MPO-dependent nitration and chlorination both proceed with Tyr-166 as a secondary site and with Tyr-236 and Tyr-29 modified only minimally. Parallel functional studies demonstrated dose-dependent losses of ABCA1-dependent cholesterol acceptor and lipid binding activities with apoA-I modification by MPO. Finally tandem mass spectrometry analyses showed that apoA-I in human atherosclerotic tissue is nitrated at the MPO-preferred sites, Tyr-192 and Tyr-166. The present studies suggest that site-specific modifications of apoA-I by MPO are associated with impaired lipid binding and ABCA1-dependent cholesterol acceptor functions, providing a molecular mechanism that likely contributes to the clinical link between MPO levels and cardiovascular disease risk.
Received for publication, June 23, 2004 , and in revised form, October 20, 2004.
* This work was supported by National Institutes of Health Grants PO1 HL076491, HL70621, HL077692, and HL66082 and American Heart Association Grant 0415089B. Mass spectrometry experiments were performed in the Mass Spectrometry Facilities of the Cleveland Clinic Foundation. Instrumentation used in these laboratories was purchased with funding from National Institutes of Health Grants RR16794 and RR15794 and the State of Ohio Hayes Investment Trust Fund. Support was also provided by the General Clinical Research Center of the Cleveland Clinic Foundation under NIH Grant RR018390. 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.
To whom correspondence should be addressed. Tel.: 216-444-7170; Fax: 216-444-9404; E-mail: kinterm{at}ccf.org.
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