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(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

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