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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1790.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Increased Cholesterol Efflux in Apolipoprotein AI (ApoAI)–Producing Macrophages as a Mechanism for Reduced Atherosclerosis in ApoAI^(-/-) Mice

Amy S. Major; Dwayne E. Dove; Hiroyuki Ishiguro; Yan Ru Su; Abigail M. Brown; Lily Liu; Kathy J. Carter; MacRae F. Linton; Sergio Fazio

From the Departments of Medicine (A.S.M., H.I., Y.R.S., A.M.B., L.L., K.J.C., M.F.L., S.F.), Pharmacology (M.F.L.), and Pathology (D.E.D., S.F.), Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Drs Sergio Fazio or MacRae F. Linton, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 315 Medical Research Building II, Nashville, TN 37232-6300. E-mail sergio.fazio{at}mcmail.vanderbilt.edu or macrae.linton@mcmail.vanderbilt.edu

Abstract—— The concentration of apolipoprotein (apo) AI in the artery wall is thought to enhance cellular cholesterol efflux and protect against atherosclerosis. It has been shown that although macrophages do not make apoAI, they respond to it by increased cholesterol efflux. We hypothesized that macrophage production of apoAI would increase cholesterol efflux and reduce atherogenesis. In this study, we produced mice expressing human apoAI under the control of the macrophage-specific scavenger receptor-A promoter (m-AI). Human apoAI was detectable in the serum HDL fraction of m-AI transgenic mice at concentrations too low to affect serum cholesterol or HDL levels. Immunoblotting showed the presence of human apoAI in transgenic macrophage culture supernatants, mostly as lipoprotein-free protein, with a small component associated with HDL-like particles. Atherosclerosis studies using apoAI^(-/-) mice transplanted with m-AI bone marrow showed that in the absence of macrophage-derived apoE, local expression of apoAI reduced diet-induced lesions in the proximal aorta. Additionally, m-AI macrophages showed a 40% increase in cholesterol efflux compared with control macrophages. These data support the hypothesis that apoAI production by macrophages in the artery wall is protective against atherosclerosis. This protection is likely mediated by increased cholesterol efflux and decreased foam cell formation in vivo.

Key Words: apoAI • transgenic mice • macrophage • foam cell

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