Background: The pathogenic mechanism of homocysteine’s effect on cardiovascular risk is poorly understood. Recent studies show that DNA hypomethylation induced by increases in S-adenosylhomocysteine (AdoHcy), an intermediate of Hcy metabolism and a potent inhibitor of methyltransferases, may be involved in homocysteine-related pathology. Methods: We measured fasting plasma total Hcy (tHcy), AdoHcy, and S-adenosylmethionine (AdoMet) and methylation in leukocytes in 17 patients with vascular disease and in 15 healthy, age- and sex-matched controls. Results: Patient with vascular disease had significantly higher plasma tHcy and AdoHcy concentrations and significantly lower plasma AdoMet/AdoHcy ratios and genomic DNA methylation. AdoMet concentrations were not significantly different between the two groups. More than 50% of the patients fell into the highest quartiles of plasma tHcy, AdoHcy, and [³H]dCTP incorporation/μg of DNA (meaning the lowest quartile of DNA methylation status) and into the lowest quartile of the AdoMet/AdoHcy ratios of the control group. Plasma tHcy was significantly correlated with plasma AdoHcy and AdoMet/AdoHcy ratios (n = 32; P < 0.001). DNA methylation status was significantly correlated with plasma tHcy and AdoHcy (n = 32; P < 0.01) but not with plasma AdoMet/AdoHcy ratios. Conclusion: Global DNA methylation may be altered in vascular disease, with a concomitant increase in plasma tHcy and AdoHcy.

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered a risk factor for atherosclerosis and cardiovascular disease (CVD), but the molecular basis of these associations remains elusive. The impairment of endothelial function, a key initial event in the setting of atherosclerosis and CVD, is recurrently observed in hyperhomocysteinemia (HHcy). Various observations may explain the vascular toxicity associated with HHcy. For instance, Hcy interferes with the production of nitric oxide (NO), a gaseous master regulator of endothelial homeostasis. Moreover, Hcy deregulates the signaling pathways associated with another essential endothelial gasotransmitter: hydrogen sulfide. Hcy also mediates the loss of critical endothelial antioxidant systems and increases the intracellular concentration of reactive oxygen species (ROS) yielding oxidative stress. ROS disturb lipoprotein metabolism, contributing to the growth of atherosclerotic vascular lesions. Moreover, excess Hcy maybe be indirectly incorporated into proteins, a process referred to as protein N-homocysteinylation, inducing vascular damage. Lastly, cellular hypomethylation caused by build-up of S-adenosylhomocysteine (AdoHcy) also contributes to the molecular basis of Hcy-induced vascular toxicity, a mechanism that has merited our attention in particular. AdoHcy is the metabolic precursor of Hcy, which accumulates in the setting of HHcy and is a negative regulator of most cell methyltransferases. In this review, we examine the biosynthesis and catabolism of Hcy and critically revise recent findings linking disruption of this metabolism and endothelial dysfunction, emphasizing the impact of HHcy on endothelial cell methylation status.