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Effects of folic acid and its active metabolite 5-methyl-tetrahydrofolic acid on endothelial function, superoxide production and gene expression in human atherosclerosis

Objective

Endothelial dysfunction is believed to be a major step in atherogenesis. Decreased nitric oxide (NO) bioavailability in human vessels may be the result of both increased oxidative deactivation or decreased production by endothelial nitric oxide synthase (e NOS) in human endothelium.

Furthermore, deficiency of tetrahydrobiopterin (BH4), a cofactor for eNOS, leads to eNOS uncoupling, making vascular endothelium a source of superoxide anions. Evidence suggests that folic acid may improve endothelial function, but the underlying mechanisms of this effect remain obscure. In the present study we aim to investigate the effects of folic acid on human vessels.

The population of the study will be consisted of 120 patients with coronary artery disease undergoing coronary artery bypass grafting (CABG) operation. Twenty patients will be treated for 6 weeks before their CABG with folic acid 5mg/day, 20 with folic acid 400g day and 20 with placebo, while 60 patients will participate in the in vitro part of the study. The experiments will be contacted in human saphenous veins, radial arteries and internal mammary arteries derived from these patients during grafts harvesting.

Particularly, we will examine the effect of chronic treatment with folic acid on endothelial function, superoxide production and multiple gene expression (using micro arrays technology) in human vessels. Furthermore we will examine the acute effect of 5methyltetrahydrofolic acid (5MTHF), the active form of folic acid, on endothelial function, superoxide production and BH4 levels in human vessels in vitro.

Additionally, we will examine the ability of 5MTHF to scavenge superoxide directly, as well as its effect on BH4 levels in endothelial cells cultures. Finally we will investigate the ability of circulating markers of oxidative stress, inflammatory process and endothelial cell injury and activation, to indirectly estimate tissue superoxide production in patients with coronary artery disease.

Call for proposal

FP6-2004-MOBILITY-5
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Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships

Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Address
University Offices Wellington Square
Oxford
United Kingdom