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

• Published in: Atherosclerosis Vol. 197; no. 2; pp. 620 - 629
• Main Authors: Thampi, Prajitha, Stewart, Bradford W, Joseph, Lija, Melnyk, Stepan B, Hennings, Leah J, Nagarajan, Shanmugam
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.04.2008; Elsevier
• Subjects: Animals; Apolipoproteins E - genetics; Associated diseases and complications; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; CD36; CD36 Antigens - metabolism; Cells, Cultured; Diabetes. Impaired glucose tolerance; Diet, Atherogenic; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelial Cells - metabolism; Female; Foam cells; Foam Cells - metabolism; Homocysteine; Homocysteine - physiology; Humans; Lipoproteins, LDL - metabolism; LOX-1; Medical sciences; Mice; Mice, Knockout; Scavenger receptors; Scavenger Receptors, Class E - metabolism; Umbilical Veins - cytology; lectin-like oxidized LDL binding protein-1; apoE; 3,3′-diaminobenzidine; LOX-1; CBS; cystathionine β-synthase; Atherosclerosis; oxLDL; Scavenger receptors; HcyBSA; oxidized LDL; CD36; ApoB; apolipoprotein E knockout; HcyLDL; Foam cells; homocysteine; DAB; Hcy-modified LDL; Hcy-modified BSA; NC; SR-A; scavenger receptor-AI/II; apolipoprotein B; Hcy; normal rodent chow; Homocysteine; Thiol; Rodentia; Cardiovascular disease; Foam cell; Sulfur containing aminoacid; Vascular disease; Vertebrata; Mammalia; Homocystein; Mouse; Animal; κ Atherosclerosis
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2007.09.014

Abstract Elevated plasma homocysteine (Hcy) 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 Hcy 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 Hcy 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 Hcy-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 Hcy nor HcyLDL directly affect the expression of CD36 and LOX-1 on mouse macrophages. However, Hcy 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 Hcy 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 Hcy may upregulate CD36 expression at the lesion site. Further, these findings suggest a novel mechanism by which Hcy may promote atherogenesis.