Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression

Elevated plasma homocysteine (Hey) levels have been recognized as an independent risk factor for atherosclerosis leading to cardiovascular diseases. However, the mechanisms contributing to atherosclerosis have not been delineated. Since, scavenger receptors mediated uptake of oxidized-LDL (oxLDL) by macrophages resulting in foam cell formation is an early event in atherosclerosis, we hypothesized that atherogenic effects of Hey may be mediated via regulating expression of scavenger receptor(s). We have tested this hypothesis using apoE-/- female mice fed normal rodent chow (NC) diet or NC supplemented with Hey in drinking water (9 g/L). Hcy-fed mice showed increased fatty streak lesions in aortic sinus/root compared to NC group without alterations in plasma lipid profiles. Similar findings were observed in the enface analysis of the descending aorta. To determine the molecular mechanisms underlying Hey-mediated progression of fatty streak lesions, expression of scavenger receptors such as CD36 and lectin-like oxidized LDL binding protein-1 (LOX-1) in the aortic lesions were analyzed. Interestingly, Hcy-fed mice had increased immuno-positive staining for CD36 and LOX-1 in the atherosclerotic lesions compared to NC-fed mice. In vitro analyses showed neither Hey nor HcyLDL directly affect the expression of CD36 and LOX-1 on mouse macrophages. However, Hey supplementation in apoE-/- mice resulted in elevated oxLDL levels in plasma. Since oxLDL has been shown to upregulate the expression of CD36 and LOX-1, these findings suggest that Hey may exert its atherogenic effect in part by elevating the levels of oxLDL. Interestingly, interaction of monocytes with Hcy-activated endothelial cells resulted in upregulation of CD36 expression on monocytes, suggesting a possible mechanism by which Hey may upregulate CD36 expression at the lesion site. Further, these findings suggest a novel mechanism by which Hey may promote atherogenesis. (C) 2007 Elsevier Ireland Ltd. All rights reserved.