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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1496.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Macrophage Reverse Cholesterol Transport in Mice Expressing ApoA-I Milano

Eric T. Alexander; Ginny L. Weibel; Michelle R. Joshi; Charulatha Vedhachalam; Margarita de la Llera-Moya; George H. Rothblat; Michael C. Phillips; Daniel J. Rader

From the Lipid Research Group (E.T.A., G.L.W., M.R.J., C.V., G.H.R., M.C.P.), the Children’s Hospital of Philadelphia, and the Department of Medicine (D.J.R.), University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Dr Daniel J. Rader, University of Pennsylvania Medical Center, 654 Biomedical Research Building II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail rader{at}mail.med.upenn.edu

Objective— To compare the abilities of human wild-type apoA-I (WT apoA-I) and human apoA-I_Milano (apoA-I_M) to promote macrophage reverse cholesterol transport (RCT) in apoA-I–null mice infected with adeno-associated virus (AAV) expressing either WT apoA-I or apoA-I_M.

Methods and Results— WT apoA-I– or apoA-I_M–expressing mice were intraperitoneally injected with [H³]cholesterol-labeled J774 mouse macrophages. After 48 hours, no significant difference was detected in the amount of cholesterol removed from the macrophages and deposited in the feces via the RCT pathway between the WT apoA-I and apoA-I_M groups. Analysis of the individual components of the RCT pathway demonstrated that the apoA-I_M–expressing mice promoted ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux as efficiently as WT apoA-I but that apoA-I_M had a reduced ability to promote cholesterol esterification via lecithin cholesterol-acyltransferase (LCAT). This resulted in reduced cholesteryl ester (CE) and increased free cholesterol (FC) levels in the plasma of mice expressing apoA-I_M compared to WT apoA-I. These differences did not affect the rate of delivery of labeled cholesterol to the liver via SR-BI–mediated selective uptake or its subsequent excretion in the feces.

Conclusion— Within the limits of the in vivo assay, WT apoA-I and apoA-I_M are equally efficient at promoting macrophage RCT, suggesting that if apoA-I_M is more atheroprotective than WT apoA-I it is not attributable to an enhancement of macrophage RCT.

The abilities of WT apoA-I and apoA-I_Milano to promote macrophage RCT in vivo in a murine model were compared. It was determined that both forms of apoA-I were equally efficient at promoting macrophage RCT.

Key Words: apoA-I Milano • reverse cholesterol transport • high-density lipoprotein • macrophage • apolipoprotein