Folic acid treatment reduces chemokine release from peripheral blood mononuclear cells in hyperhomocysteinemic subjects.
Elevated plasma homocysteine concentration is an independent risk factor for cardiovascular disease. However, the mechanisms by which hyperhomocysteinemia induces vascular disease are uncertain. An early step in atherogenesis involves leukocyte migration into the arterial wall, a process regulated in part by chemokines. We hypothesized that homocysteine may exert its atherogenic effect in part through chemokine-mediated mechanisms, and in the present study, we examined the effects of folic acid supplementation for 6 weeks on chemokine levels in hyperhomocysteinemic individuals. Data showed the following: (1) Compared with control subjects, hyperhomocysteinemic subjects had elevated plasma levels of the CXC chemokines, epithelial neutrophil-activating peptide (ENA)-78 (P<0.05), and growth-regulated oncogene (GRO)alpha (P=0.088), and homocysteine was significantly correlated with ENA-78 and GROalpha. (2) During folic acid treatment, normalization of homocysteine levels was accompanied by a marked reduction in oxidized low density lipoprotein-stimulated release of CXC chemokines (ie, GROalpha, ENA-78, and interleukin-8) and CC chemokines (ie, monocyte chemoattractant peptide-1 and RANTES) in peripheral blood mononuclear cells from these individuals. (3) The oxidized low density lipoprotein-induced release of ENA-78 from peripheral blood mononuclear cells from control subjects was significantly reduced when cells were incubated in the presence of folic acid. These data may suggest that homocysteine exerts atherogenic effects in part by enhancing chemokine responses in cells involved in atherogenesis and that folic acid supplementation may downregulate these inflammatory responses.
Holven
Kirsten B
KB
Lipid Clinic, MSD Cardiovascular Research Center, Research Institute for Internal Medicine, Section of Clinical Immunology, Medical Department, Division of Heart and Lung Diseases, Rikshospitalet University Hospital, Oslo, Norway.
Aukrust
Pål
P
Holm
Torbjørn
T
Ose
Leiv
L
Nenseter
Marit S
MS
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018946:Chemokine CCL5 / Q000097:blood; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D018925:Chemokines / Q000097:blood*; D019743:Chemokines, CXC / Q000097:blood; D002630:Chemotactic Factors / Q000097:blood; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D006133:Growth Substances / Q000097:blood; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood*; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000031:analogs & derivatives* / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged
C475829:CXCL1 protein, human; C486263:CXCL5 protein, human; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D006710:Homocysteine; D005492:Folic Acid