OBJECTIVE: To investigate the association of antioxidant intakes from diet and supplements with elevated blood C-reactive protein (CRP) and homocysteine (Hcy) concentrations. DESIGN: A cross-sectional study. The main exposures were vitamins C and E, carotene, flavonoid and Se intakes from diet and supplements. Elevated blood CRP and Hcy concentrations were the outcome measures. SETTING: The US population and its subgroups. SUBJECTS: We included 8335 US adults aged≥19 years from the National Health and Nutrition Examination Survey 1999-2002. RESULTS: In this US population, the mean serum CRP concentration was 4·14 (95 % CI 3·91, 4·37) mg/l. Intakes of vitamins C and E and carotene were inversely associated with the probability of having serum CRP concentrations>3 mg/l in multivariate logistic regression models. Flavonoid and Se intakes were not associated with the odds of elevated serum CRP concentrations. The mean plasma Hcy concentration was 8·61 (95 % CI 8·48, 8·74) μmol/l. Intakes of vitamins C, E, carotenes and Se were inversely associated with the odds of plasma Hcy concentrations>13μmol/l after adjusting for covariates. Flavonoid intake was not associated with the chance of elevated plasma Hcy concentrations. CONCLUSIONS: These results suggest that high antioxidant intake is associated with lower blood concentrations of CRP and Hcy. These inverse associations may be among thepotential mechanisms for the beneficial effect of antioxidant intake on CVD risk mediators in observational studies.

Hyperhomocysteinemia is a recognized risk factor for vascular disease, but pathogenetic mechanisms involved in its vascular actions are largely unknown. Because VCAM-1 expression is crucial in monocyte adhesion and early atherogenesis, we evaluated the NF-kappaB-related induction of VCAM-1 by homocysteine (Hcy) and the possible inhibitory effect of dietary polyphenolic antioxidants, such as trans-resveratrol (RSV) and hydroxytyrosol (HT), which are known inhibitors of NF-kappaB-mediated VCAM-1 induction. In human umbilical vein endothelial cells (HUVEC), Hcy, at 100 micromol/l, but not cysteine, induced VCAM-1 expression at the protein and mRNA levels, as shown by enzyme immunoassay and Northern analysis, respectively. Transfection studies with deletional VCAM-1 promoter constructs demonstrated that the two tandem NF-kappaB motifs in the VCAM-1 promoter are necessary for Hcy-induced VCAM-1 gene expression. Hcy-induced NF-kappaB activation was confirmed by EMSA, as shown by the nuclear translocation of its p65 (RelA) subunit and the degradation of the inhibitors IkappaB-alpha and IkappaB-beta by Western analysis. Hcy also increased intracellular reactive oxygen species by NAD(P)H oxidase activation, as shown by the membrane translocation of its p47(phox) subunit. NF-kappaB inhibitors decreased Hcy-induced intracellular reactive oxygen species and VCAM-1 expression. Finally, we found that nutritionally relevant concentrations of RSV and HT, but not folate and vitamin B6, reduce (by>60% at 10(-6) mol/l) Hcy-induced VCAM-1 expression and monocytoid cell adhesion to the endothelium. These data indicate that pathophysiologically relevant Hcy concentrations induce VCAM-1 expression through a prooxidant mechanism involving NF-kappaB. Natural Mediterranean diet antioxidants can inhibit such activation, suggesting their possible therapeutic role in Hcy-induced vascular damage.

Prevalence of mild hyperhomocysteinemia in vegetarians and vegans is a consequence of vitamin B12 deficiency. Clinical study of homocysteine reduction by vitamin B12 consisted of subjective healthy adults on alternative nutrition (n = 9) with vitamin B12 deficiency and with mild hyperhomocysteinemia. Vitamin B12 treatment was implemented by 5 intramuscular cyanocobalamin injections of a total content of 2200 micrograms during two weeks. Homocysteine level was significantly reduced (from 22 mumol/l to 11.7 mumol/l; individual reduction 29-55%). Vitamin B12 concentration in blood was significantly increased (from 152 pmol/l to 277 pmol/l; individual % of increase 63-150). The results show a high effect of vitamin B12 treatment in homocysteine value reduction of subjects on alternative nutrition.