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.

CD36: Implications in cardiovascular disease

“…Because of recognition of the extensive remodeling at the aortic sinus, we have felt that it is more appropriate to measure aortic tree lesion area to assess atherosclerosis extent in Western diet fed mice in our studies. Re-examination of the data of Moore et al (2005) then shows similar results to what we reported in the aortic tree; the difference in males may manifest more strongly at 12 weeks rather than 8 weeks.…”

“…The view that scavenger receptors (specifically CD36 and SRA) contribute to foam cell formation, particularly in a pro-inflammatory setting, which promotes lipoprotein modifications that enhance their specific recognition by such receptors, was questioned recently in a report by Moore et al (2005). In that study, CD36/apoE double KO mice were fed a Western diet for 8 weeks and lesions evaluated at both the aortic sinus and throughout the aortic tree.…”

“…The creation of the CD36 knock out (KO) mouse and subsequent crossing to other murine mutants has enabled many of these studies (Febbraio, et al, 1999). Apart from a recent publication (Moore, et al, 2005) suggesting that CD36 expression is beneficial in the pathogenesis of atherosclerosis (which we will address specifically), the consensus of the literature is that macrophage CD36 plays a major role in the uptake of pro-atherogenic lipoproteins, and in the absence of up-regulation of efflux mechanisms, this results in foam cell formation, the initiating lesion in atherosclerosis. This review will focus on CD36 as it relates to the cardiovascular system, and thus is not meant to be exhaustive and will omit ligands and functions that may not be pertinent to this focus.…”

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

“…Among these SRs, the type A scavenger receptor (SRA) and CD36, a member of the type B family, have been extensively studied (Kunjathoor et al, 2002). It is well known that ApoE-deficient mice, which are widely used as a model of atherosclerosis, develop atherosclerotic lesions throughout the arterial tree (Moore et al, 2005;Manning-Tobin et al, 2009). Interestingly, mice with CD36 and ApoE double deficiency show reduced atherosclerotic lesions and greatly reduced uptake of oxLDL by macrophages compared with their littermate controls © Higher Education Press and Springer-Verlag Berlin Heidelberg 2012 (Podrez et al, 2000).…”

Mechanisms by which diabetes increases cardiovascular disease

“…Furthermore, AGE induce endothelial hyperpermeability and have been shown to be chemotactic for monocytes in vitro and in vivo [17]. Although the role of scavenger receptors in atherogenesis is controversial [19], induction of scavenger receptor class A and CD36 in macrophages due to AGE may represent another pro-atherogenic mechanism [17]. In summary, AGE formation due to hyperglycemia may promote development of atherosclerotic lesions by various well-known pro-atherogenic receptors [20].…”