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Nutritional Immunology
Research Communication

Hyperhomocysteinemic Subjects Have Enhanced Expression of Lectin-Like Oxidized LDL Receptor-1 in Mononuclear Cells¹

Kirsten B. Holven^*,,**, Hanne Scholz^**, Bente Halvorsen^**, Pål Aukrust^**,, Leiv Ose^* and Marit S. Nenseter^*,,**,2

^* The Lipid Clinic, MSD Cardiovascular Research Center, ^** Research Institute for Internal Medicine and Section of Clinical Immunology and Infection Diseases, Medical Department, Rikshospitalet University Hospital, Oslo, Norway

²To whom correspondence should be addressed. E-mail: maritn{at}klinmed.uio.no.

An elevated plasma concentration of homocysteine is an independent risk factor for cardiovascular disease. However, the mechanisms are still unclear. Lectin-like oxidized LDL receptor-1 (LOX-1) has ligand specificity for oxidized LDL (oxLDL). We hypothesized that homocysteine’s atherogenic effects may involve LOX-1-mediated mechanisms. We examined the effect of folic acid supplementation for 6 wk and 12 mo (5 mg/d for 1 wk, 1 mg/d for 37 wk and 0.4 mg/d for the remaining 14 wk) on LOX-1 mRNA levels and on oxLDL-induced release of tumor necrosis factor from peripheral blood mononuclear cells in hyperhomocysteinemic individuals. Compared with healthy controls, hyperhomocysteinemic subjects had elevated mRNA levels of LOX-1 in mononuclear cells (P < 0.001), and their mononuclear cells released more tumor necrosis factor (TNF) upon oxLDL stimulation (P = 0.01). This oxLDL-stimulated release of TNF correlated with LOX-1 expression (r = 0.57, P = 0.026). Folic acid treatment led to a normalization of homocysteine levels accompanied by a reduction in LOX-1 gene expression (P < 0.02) and in oxLDL-stimulated release of TNF (P < 0.05). These novel findings suggest both that homocysteine exerts its atherogenic effect in part by elevating levels of LOX-1, thereby enhancing oxLDL-induced inflammatory responses, and most important, that folic acid supplementation may downregulate these responses.

KEY WORDS: • homocysteine • folic acid • chemokines • PBMC • inflammation

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