Homocysteine and reactive oxygen species in metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: The pleiotropic effects of folate supplementation

There are multiple metabolic toxicities resulting in an excess of reactive oxygen species associated with MS, T2DM, and the accelerated atherosclerosis (atheroscleropathy). HHcy is associated with an increased risk of cardiovascular disease, and its individual role and how it interacts with the other multiple toxicities are presented.The water-soluble B vitamins (especially folate and cobalamin-vitamin B12) have been shown to lower HHcy. The absence of the cystathionine beta synthase enzyme in human vascular cells contributes to the importance of a dual role of folic acid in lowering tHcy through remethylation, as well as, its action of being an electron and hydrogen donor to the essential cofactor tetrahydrobiopterin. This folate shuttle facilitates the important recoupling of the uncoupled endothelial nitric oxide synthase enzyme reaction and may restore the synthesis of the omnipotent endothelial nitric oxide to the vasculature.Homocysteine (Hcy) is a nonessential sulfur-containing amino acid and an intermediary metabolic product derived from the demethylated essential amino acid methionine (figure 1).Since its discovery in 1932 by the 1955 Nobel Prize recipient Vincent DuVigneaud [1] and its association with premature arteriosclerotic (fibrotic) vascular disease described by Kilmer McCully in 1969 [2], Hcy has emerged as a novel marker of risk for cardiovascular disease.In the past decade Hcy has become widely accepted as a novel risk marker associated with atherosclerotic cardiovascular disease (CVD) in the coronary, cerebral, and peripheral vascular beds. Additionally, it has been determined that hyperhomocysteinemia (HHcy) is an independent and a graded risk factor for the development of CVD [3-13]. The current role of Hcy as a causative factor still remains controversial and needs to be more fully elucidated.The important role of oxidative – redox stress and HHcy is biologically plausible because Hcy promotes oxidant injury to vascular cells (particularly th