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A model system is presented using human umbilical vein endothelial cells (HUVECs) to investigate the role of homocysteine (Hcy) in atherosclerosis. HUVECs are shown to export Hcy at a rate determined by the flux through the methionine/Hcy pathway. Additional methionine increases intracellular methionine, decreases intracellular folate, and increases Hcy export, whereas additional folate inhibits export. An inverse relationship exists between intracellular folate and Hcy export. Hcy export may be regulated by intracellular S-adenosyl methionine rather than by Hcy. Human LDLs exposed to HUVECs exporting Hcy undergo time-related lipid oxidation, a process inhibited by the thiol trap dithionitrobenzoate. This is likely to be related to the generation of hydroxyl radicals, which we show are associated with Hcy export. Although Hcy is the major oxidant, cysteine also contributes, as shown by the effect of glutamate. Finally, the LDL oxidized in this system showed a time-dependent increase in uptake by human macrophages, implying an upregulation of the scavenger receptor. These results suggest that continuous export of Hcy from endothelial cells contributes to the generation of extracellular hydroxyl radicals, with associated oxidative modification of LDL and incorporation into macrophages, a key step in atherosclerosis. Factors that regulate intracellular Hcy metabolism modulate these effects.

Background: The oxidative modification of LDL is thought to play a crucial role in the initiation of atherosclerosis. Antioxidant vitamins can protect LDL from oxidation, and high intakes or blood concentrations of these vitamins have been linked with a reduced risk of cardiovascular disease. Few data are available on the importance of antioxidant vitamins in earlier stages of atherogenesis., Objective: We investigated the cross-sectional relation between antioxidant vitamin status and carotid atherosclerosis in a group of elderly persons., Design: The study sample comprised 468 men and women aged 66-75 y living in Sheffield, United Kingdom. Duplex ultrasonography was used to measure intima-media thickness and the degree of stenosis in the extracranial carotid arteries. Antioxidant vitamin status was assessed by measuring fasting plasma concentrations of vitamin C, vitamin E, and beta-carotene., Results: In the men, after adjustment for age and cardiovascular disease risk factors, a 20% higher plasma vitamin C concentration was associated with a 0.004-mm smaller intima-media thickness; a 20% higher beta-carotene concentration was associated with a 0.005-mm smaller intima-media thickness. Compared with men with high blood concentrations of beta-carotene or cholesterol-adjusted vitamin E, those with low blood concentrations of these vitamins were 2.5 times as likely to have carotid stenosis of >30%. We found no significant trends between plasma concentrations of antioxidant vitamins and either measure of carotid atherosclerosis in the women., Conclusion: A high antioxidant vitamin status may help to prevent the initiation and progression of early atherosclerotic lesions in men.

During gestation iron is diverted from maternal tissues to satisfy fetal requirements, but the factors controlling this transfer are not well understood. Riboflavin may be important in this process, because it is believed to be involved in the mobilization of iron from tissue ferritin. An experiment was designed to test this possibility. Female Norwegian Hooded rats were fed a riboflavin-deficient diet (B2-) from 10 wk of age through to mating and gestation. Control animals fed a complete diet (B2+) were weight-matched to the rats fed the B2- diet. At d 17 or 20 of gestation 59Fe was administered to the dam, and distribution of 59Fe between maternal, placental and fetal tissues was determined 24 h later. Iron-mobilizing activity in placental mitochondria preparations was reduced in riboflavin-deficient rats at d 18 of gestation. Riboflavin deficiency was associated with a reduction in the percentage of the radioiron dose reaching the fetal tissue at both stages of gestation. Maternal hepatic iron stores and plasma iron levels were greater in B2- dams than in controls at d 18 of gestation and showed a reduced rate of depletion over the subsequent 3 d. However, concentrations of radioiron and of ferritin iron and nonheme iron in the fetal tissues were unaffected by riboflavin status. The primary effect of riboflavin deficiency appeared to be a reduction in fetal mass, which served to limit maternal iron depletion and maternofetal iron transfer.

Riboflavin status was measured by activation coefficient of erythrocyte glutathione reductase (EGRAC) in elderly and adolescent rural Gambians whose intakes were low. Fifty-one adolescents and 52 elderly subjects were each subdivided into six supplementation groups to receive 0.25, 0.5, 0.75, 1.0, 1.5, or 2.5 mg riboflavin/d on 5 consecutive days weekly for 5 wk. Before supplementation, EGRAC values were grossly abnormal and differed (p less than 0.005) between the two female groups [elderly subjects, 1.94 +/- 0.33 (means +/- SD); adolescents. 1.72 +/- 0.27] but not between the two male groups. With supplementation greater than 0.25 mg/d the values became nearly equal in the two age groups. Only at total intakes between 1.8 and 2.5 mg riboflavin/d did the subjects attain acceptable status, with a mean EGRAC of 1.3-1.4. Clearly there is a need for further study of the discrepancy between observed index values during supplementation and the accepted ranges of normality at intakes close to the recommended amounts.

Combined marginal deficiencies of iron, vitamin C, and B-group vitamins are widespread in developing countries. An understanding of the functional implications poses a continuing challenge, both for the development of new techniques of investigation and for the design of effective intervention programmes. Practical intervention in developing countries also needs to take account of the interactions of micronutrient status and disease susceptibility. It is becoming clear that combined deficiencies of certain vitamins, or of iron and vitamins, although less severe than those causing the lesions of classic clinical deficiency, can seriously reduce work performance. Riboflavin, particularly, has a special relation with iron economy.