Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice
Kathryn J. Moore, … , Mary McKee, Mason W. Freeman
Kathryn J. Moore, … , Mary McKee, Mason W. Freeman
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2192-2201. https://doi.org/10.1172/JCI24061.
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Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice

Abstract

Macrophage internalization of modified lipoproteins is thought to play a critical role in the initiation of atherogenesis. Two scavenger receptors, scavenger receptor A (SR-A) and CD36, have been centrally implicated in this lipid uptake process. Previous studies showed that these receptors mediated the majority of cholesterol ester accumulation in macrophages exposed to oxidized LDL and that mice with deletions of either receptor exhibited marked reductions in atherosclerosis. This work has contributed to an atherosclerosis paradigm: scavenger receptor–mediated oxidized lipoprotein uptake is required for foam cell formation and atherogenesis. In this study, Apoe–/– mice lacking SR-A or CD36, backcrossed into the C57BL/6 strain for 7 generations, were fed an atherogenic diet for 8 weeks. Hyperlipidemic Cd36–/–Apoe–/– and Msr1–/–Apoe–/– mice showed significant reductions in peritoneal macrophage lipid accumulation in vivo; however, in contrast with previous reports, this was associated with increased aortic sinus lesion areas. Characterization of aortic sinus lesions by electron microscopy and immunohistochemistry showed abundant macrophage foam cells, indicating that lipid uptake by intimal macrophages occurs in the absence of CD36 or SR-A. These data show that alternative lipid uptake mechanisms may contribute to macrophage cholesterol ester accumulation in vivo and suggest that the roles of SR-A and CD36 as proatherosclerotic mediators of modified LDL uptake in vivo need to be reassessed.

Authors

Kathryn J. Moore, Vidya V. Kunjathoor, Stephanie L. Koehn, Jennifer J. Manning, Anita A. Tseng, Jessica M. Silver, Mary McKee, Mason W. Freeman

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Figure 3

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Morphometric analysis of lesion area in the aortic tree. Aortae were sta...
Morphometric analysis of lesion area in the aortic tree. Aortae were stained en face with Sudan IV, and lesion area was measured as a percentage of total aortic area. (A) Lesion area in male and female mice. *P ≤ 0.05; significantly different from Apoe–/– control mice. (B) Representative photographs of the en face aortae from female Apoe–/–, Cd36–/–Apoe–/–, and Msr1–/–Apoe–/– mice. The boxed region indicates the area of reduced lesions observed in the Cd36–/–Apoe–/– female mice.