This Article Full Text Full Text (PDF) All Versions of this Article: 23/9/1583    most recent 01.ATV.0000085840.67498.00v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Macdonald, D. L. Articles by Francis, G. A. Search for Related Content PubMed PubMed Citation Articles by Macdonald, D. L. Articles by Francis, G. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL L-TYROSINE Related Collections Cardiovascular imaging agents/Techniques ACE/Angiotension receptors Coagulation and fibronolysis Endothelium/vascular type/nitric oxide

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1583.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Administration of Tyrosyl Radical–Oxidized HDL Inhibits the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Dawn L. Macdonald; Timothy L. Terry; Luis B. Agellon; Patrick N. Nation; Gordon A. Francis

From the CIHR Group on Molecular and Cell Biology of Lipids and Departments of Medicine (D.L.M., T.L.T, G.A.F) and Biochemistry (L.B.A., G.A.F.) and Department of Laboratory Medicine and Pathology (P.N.N.), University of Alberta, Edmonton, Alberta, Canada.

Correspondence to Gordon A. Francis, MD, 328 HMRC, University of Alberta, Edmonton, AB, Canada T6G 2S2. E-mail gordon.francis{at}ualberta.ca

Objective— Tyrosyl radical–oxidized HDL (tyrHDL) increases the ability of cells to donate cholesterol to apolipoprotein (apo) A-I for HDL particle formation. We tested whether treatment with tyrHDL raises endogenous HDL cholesterol levels and decreases atherosclerosis development in apoE-deficient mice.

Methods and Results— Tyrosyl radical oxidation of mouse HDL induced formation of apoAI-AII heterodimers and enhanced the ability of mouse HDL to deplete cultured fibroblasts of their regulatory pool of cholesterol. ¹²⁵I-labeled HDL and tyrHDL delivered intraperitoneally were cleared at similar rates from plasma of chow-fed apoE-deficient mice. ApoE-deficient mice injected intraperitoneally twice weekly with 150 µg tyrHDL from age 10 to 18 weeks showed a maximum 2.3-fold increase in endogenous HDL cholesterol levels, which fell toward the end of the treatment period. tyrHDL treatment resulted in 37% less aortic lesion development than in control HDL-treated mice (P<0.001) and 67% less than in saline-injected animals (P<0.001).

Conclusions— Administration of tyrHDL for 8 weeks resulted in significantly less atherosclerosis development in apoE-deficient mice than injection of HDL or saline. Molecules increasing mobilization of cellular cholesterol to apoAI for HDL particle formation would be expected to decrease atherosclerosis without necessarily causing sustained increases in circulating HDL cholesterol levels.

Key Words: apolipoprotein A-I • atherosclerosis • HDL • tyrosyl radical • ABCA1

This article has been cited by other articles:

				A. Pirillo, P. Uboldi, G. Pappalardo, H. Kuhn, and A. L. Catapano Modification of HDL3 by mild oxidative stress increases ATP-binding cassette transporter 1-mediated cholesterol efflux Cardiovasc Res, August 1, 2007; 75(3): 566 - 574. [Abstract] [Full Text] [PDF]

				C. R. Sirtori HDL and the progression of atherosclerosis: new insights Eur. Heart J. Suppl., October 1, 2006; 8(suppl_F): F4 - F9. [Abstract] [Full Text] [PDF]

				B. J. Ansell, K. E. Watson, A. M. Fogelman, M. Navab, and G. C. Fonarow High-Density Lipoprotein Function: Recent Advances J. Am. Coll. Cardiol., November 15, 2005; 46(10): 1792 - 1798. [Abstract] [Full Text] [PDF]

				J. F. Oram and J. W. Heinecke ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That Protects Against Cardiovascular Disease Physiol Rev, October 1, 2005; 85(4): 1343 - 1372. [Abstract] [Full Text] [PDF]

				L. Zheng, M. Settle, G. Brubaker, D. Schmitt, S. L. Hazen, J. D. Smith, and M. Kinter 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 J. Biol. Chem., January 7, 2005; 280(1): 38 - 47. [Abstract] [Full Text] [PDF]

				M. Navab, G. M. Ananthramaiah, S. T. Reddy, B. J. Van Lenten, B. J. Ansell, G. C. Fonarow, K. Vahabzadeh, S. Hama, G. Hough, N. Kamranpour, et al. Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL J. Lipid Res., June 1, 2004; 45(6): 993 - 1007. [Abstract] [Full Text] [PDF]

				C. Bergt, J. F. Oram, and J. W. Heinecke Oxidized HDL: The Paradox-idation of Lipoproteins Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1488 - 1490. [Full Text] [PDF]