Stem Cell Transplantation Reveals That Absence of Macrophage CD36 Is Protective Against Atherosclerosis

Abstract

Objective-CD36 is expressed on multiple cell types and has numerous functions, a subset of which can impact on atherogenesis.In previous work, we demonstrated that CD36 absence was protective against lesion formation. The current objective was to determine whether absence of macrophage CD36 alone was protective. Methods and Results-Lethal irradiation and stem cell transfer were used to create chimeric mice that did or did not express macrophage CD36 in the context of the Apo E-null model of atherosclerosis. After engraftment, mice were fed a Western diet for 12 weeks. White cell counts, plasma levels of lipoproteins, triacylglycerol, and nonesterified fatty acids were determined, and glucose tolerance tests were preformed. Lesion area was assessed quantitatively after oil red O staining. Mice lacking CD36 in macrophages alone were profoundly protected against atherosclerosis (88.1% reduction of lesion area throughout the aortic tree). Re-introduction of macrophage CD36 resulted in a 2.11-fold increase in lesion area. There were no differences in engraftment, macrophage recruitment, glucose tolerance, weight, and total, low-density lipoprotein, and high-density lipoprotein cholesterol among the groups. Lesions contained similar percent macrophage antigen-positive area. Key Words: CD36 Ⅲ atherosclerosis Ⅲ Apo E-null mice Ⅲ scavenger receptor Ⅲ macrophages C ellular cholesterol homeostasis is tightly regulated such that cells have an adequate supply under varying dietary conditions. 1 For most cell types, excessive accumulation of cholesterol does not occur and would have toxic implications. 2 Macrophages, by virtue of their scavenger function, internalize cholesterol-laden modified lipoproteins. Uncontrolled cholesterol accumulation in macrophages may result as an adaptive mechanism in response to excessive lipid load and lead to foam cell formation. These appear grossly as the initial lesion in atherosclerosis, the fatty streak. 3 Oxidative modification of low-density lipoprotein (LDL) has been hypothesized to be a key event in the conversion of LDL to a pro-atherogenic form recognized by macrophage scavenger receptors. 4,5 Thus, internalization of oxidized LDL (OxLDL) by macrophages is an early and potentially pivotal event which, if inhibited through intervention at the level of the scavenger receptor, may delay the atherosclerotic process. Conclusion-ProtectionPrevious in vitro work has supported a significant role for the class B scavenger receptor, CD36, in atherogenesis. 6,7 We and others demonstrated that CD36 bound OxLDL in a saturable manner; binding, internalization, and degradation of OxLDL were increased substantially in CD36 transfected cells. 6 -8 Regulation of CD36 expression was also highly suggestive of an important role in atherosclerosis. 9 -15 Unlike the LDL receptor, which is downregulated by cellular cholesterol/cholesterol ester, expression of CD36 was enhanced by cellular cholesterol/cholesterol ester content and downregulated by its depletion. 10 We also showed that IL-4 and macrophage-c...

CD36: Implications in cardiovascular disease

“…Male but not female mice also had significantly reduced lesion area at the level of the aortic sinus on a normal chow diet . Using a bone marrow transplant approach, we showed that absence of CD36 in hematopoietic cells accounted for the protection observed in the apoE KO model (Febbraio, Guy, & Silverstein, 2004). This study was again using a 12 week Western diet regimen.…”

Receptor for Advanced Glycation End Products (RAGE) Deficiency Attenuates the Development of Atherosclerosis in Diabetes

“…Expression of the type B macrophage scavenger receptor CD36 (24) was also attenuated in diabetic RAGE Ϫ/Ϫ /apoE Ϫ/Ϫ mice. Although this change is likely to be secondary to reduced leukocyte recruitment, CD36 has been clearly demonstrated to play a proatherogenic role because the absence of macrophage CD36 protects against vascular lesion formation in mice (25). Thus, one cannot exclude that some of the antiatherosclerotic effects seen with RAGE deletion could be related to changes in the expression of CD36.…”

Nuclear receptors in macrophages: A link between metabolism and inflammation

“…There are reports suggesting that it reduces atherosclerosis in ApoE [91,92] or LDLR null mice [93,94] although others did not detect significant effects in another model of murine atherosclerosis (ApoE3 Leiden) [95]. CD36-deficient macrophages are more resistant to foam cell formation as shown in ApoE knockout mice [96,97] and by using CD36 blocking antibodies [98]. Moore and colleagues showed that the lack of SR-A or CD36 results in decreased lipid accumulation in peritoneal macrophages whilst associated with increased lesion areas in ApoE null background [99].…”