Hyperhomocysteinemic subjects have enhanced expression of lectin-like oxidized LDL receptor-1 in mononuclear cells.
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 alpha 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 alpha (TNFalpha) upon oxLDL stimulation (P = 0.01). This oxLDL-stimulated release of TNFalpha 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 TNFalpha (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.
Holven
Kirsten B
KB
The Lipid Clinic, Medical Department, Rikshospitalet University Hospital, Oslo, Norway.
Scholz
Hanne
H
Halvorsen
Bente
B
Aukrust
Pål
P
Ose
Leiv
L
Nenseter
Marit S
MS
D000328:Adult; D000368:Aged; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000097:blood* / Q000235:genetics*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C495137:OLR1 protein, human; D012333:RNA, Messenger; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D014409:Tumor Necrosis Factor-alpha; D005492:Folic Acid