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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1977.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Arg123-Tyr166 Domain of Human ApoA-I Is Critical for HDL-Mediated Inhibition of Macrophage Homing and Early Atherosclerosis in Mice

Paul Holvoet; Kathleen Peeters; Sissel Lund-Katz; Ann Mertens; Peter Verhamme; Rozenn Quarck; Dominique Stengel; Marleen Lox; Els Deridder; Hilde Bernar; Margaret Nickel; Gregor Theilmeier; Ewa Ninio; Michael C. Phillips

From the Center for Experimental Surgery and Anesthesiology (P.H., K.P., A.M., P.V., R.Q., M.L., E.D., H.B.) and the Center for Molecular and Vascular Biology (G.T.), Katholieke Universiteit Leuven, Leuven, Belgium; the Joseph Stokes Jr. Research Institute (S.L.-K., M.N., M.C.P.), The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia; and INSERM U525 (D.S., E.N.), IFR 14 "Coeur Muscle et Vaisseaux" and Faculté de Médecine Pitié, Salpêtrière/Université Pierre et Marie Curie, Paris, France. Dr Theilmeier is now at Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, University of Muenster, Muenster, Germany.

Correspondence to Paul Holvoet, PhD, Center for Experimental Surgery and Anesthesiology, University of Leuven, Campus Gasthuisberg, O & N, Herestraat 49, B-3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.ac.be

Atherosclerosis was studied in apolipoprotein E (apoE) knockout mice expressing human apolipoprotein A-I (apoA-I) or an apoA-I/apolipoprotein A-II (apoA-II) chimera in which the Arg123-Tyr166 central domain of apoA-I was substituted with the Ser12-Ala75 segment of apoA-II. High density lipoprotein (HDL) cholesterol levels were identical in apoA-I and apoA-I/apoA-II mice, but at 4 months, plaques were 2.7-fold larger in the aortic root of the apoA-I/apoA-II mice (P<0.01). The macrophage–to–smooth muscle cell ratio of lesions was 2.1-fold higher in apo-I/apoA-II mice than in apoA-I mice (P<0.01). This was due to a 2.7-fold higher (P<0.001) in vivo macrophage homing in the aortic root of apoA-I/apoA-II mice. Plasma platelet-activating factor acetyl hydrolase activity was lower (P<0.01) in apoA-I/apoA-II mice, resulting in increased oxidative stress, as evidenced by the higher titer of antibodies against oxidized low density lipoprotein (P<0.01). Increased oxidative stress resulted in increased stimulation of ex vivo macrophage adhesion by apoA-I/apoA-II ß-very low density lipoprotein and decreased inhibition of ß-very low density lipoprotein–induced adhesion by HDL from apoA-I/apoA-II mice. The cellular cholesterol efflux capacity of HDL from apoA-I/apoA-II mice was very similar to that of apoA-I mice. Thus, the Arg123-Tyr166 central domain of apoA-I is critical for reducing oxidative stress, macrophage homing, and early atherosclerosis in apoE knockout mice independent of its role in HDL production and cholesterol efflux.

Key Words: apolipoprotein A-I • HDL • atherosclerosis • oxidative stress • macrophage homing

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