Hyperhomocysteinemia acts via DNA-hypomethylation to induce atherosclerosis

Abstract

Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis responsible for chronic and acute cardiovascular events, such as myocardial infarction, stroke, and peripheral vascular disease. The aim of this review is to evaluate the mechanisms through which increased homocysteine (Hcy) ​​levels cause atherosclerotic events. It is knonw that the amino-acid Hcy, through the trans-methylation pathway, results in S-adenosyl-methionine (SAM). In turn, SAM transfers a methyl group (-CH3) to some substrates, such as DNA, turning in S-Adenosyl-Homocysteine (SAH). But, this compound is able to inhibit DNA methyltransferase (DNT), that is the enzyme responsible for DNA methylation. The consequent DNA hypomethylation favors the Cyclin A inhibition, responsible for the atherosclerotic findings. Thus, DNA hypomethylation is a risk factor for atherosclerosis rather than HHcy, that is a simple indicator of this complication. Concordantly, several reports and large trials indicate that folate (vit. B-9) and B-6-12 vitamins supplementation, even lowers HHcy levels, did not reduce the incidence of atherosclerosis. But, that can be antagonized by the product of Hcy-transsulfuration, as H2S. Conclusively, the contemporary administration of H2S + folic acid (that antagonizes HHcy) should reduce both high Hcy serum levels and cardiovascular acute events.