Folic acid says NO to vascular diseases

Objectives The possible link between folic acid or folate and tetrahydrobiopterin (H4B), vitamin C, polyunsaturated fatty acids (PUFAs), and nitric oxide (NO), which may explain the beneficial actions of these nutrients in various vascular conditions, was investigated. Methods The literature pertaining to the actions of folic acid/folate, H4B, vitamin C, PUFAs, and NO was reviewed. Results Impaired endothelial NO (eNO) activity is an early marker for cardiovascular disease. Most risk factors for atherosclerosis are associated with impaired endothelium-dependent vasodilatation due to reduced NO production. Folate not only reduces plasma homocysteine levels but also enhances eNO synthesis and shows anti-inflammatory actions. It stimulates endogenous H4B regeneration, a cofactor necessary for eNO synthesis, inhibits intracellular superoxide generation, and thus enhances the half-life of NO. H4B in turn enhances NO generation and augments arginine transport into the cells. Folic acid increases the concentration of ω-3 PUFAs, which also enhance eNO synthesis. Vitamin C augments eNO synthesis by increasing intracellular H4B and stabilization of H4B. Insulin stimulates H4B synthesis and PUFA metabolism, suppresses the production of proinflammatory cytokine tumor necrosis factor-α and superoxide anion, and enhances NO generation. The ability of folate to augment eNO generation is independent of its capacity to lower plasma homocysteine levels. Conclusions The common mechanism by which folic acid, H4B, vitamin C, ω-3 fatty acids, and -arginine bring about their beneficial actions in various vascular diseases is by enhancing eNO production. Hence, it remains to be determined whether a judicious combination of folic acid, vitamins B12, B6, and C, H4B, -arginine, and ω-3 fatty acids in appropriate amounts may form a novel approach in the prevention and management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, peripheral vascular disease, and some neurodegenerative conditions.