Hyperhomocysteinemia in the pathogenesis of cardiovascular and endocrine diseases: translational messages

Abstract

For about half a century, researchers have been particularly interested in the amino acid homocysteine (Hcys), a product of methionine dimethyl- ation. Hcys metabolism is based on two biochemical constants: remethylation and trans-sulfuration. The balance between these two mechanisms determines Hcys level in the body. For the functioning of both pathways, a sufficient concentration of vitamins B1, B6, B12 and folic acid, which act as cofactors in remethylation and transulfuration reactions, is required. Under normal conditions, Hcys is present in the human body in the range of 5-15 μmol/L and plays an important role in maintaining normal levels of the essential amino acid methionine. According to modern hypotheses, in addition to the physiological function Hcys has a pathogenetic effect. It damages the tissue structures of blood vessels, initiating the release of cytokines. The accumulation of Hcys in the blood leads to loosening of the walls of the arteries, the formation of local defects in the endothelium, increasing the risk of thrombosis. In addition, it is a potential procoagulant due to its ability to inhibit antithrombin III, protein C and activate factors V and XII, which play a particularly important role in the development of atherothrombotic and cardiogenic strokes. One of the mechanisms through which the toxic effect of Hсys is realized is through its ability to generate reactive oxygen species (ROS). In fact, possessing an active thiol group, Hcys is easily oxidized, causing the production of powerful acid radicals. Increased levels of Hcys lead to the development of ROS by inhibiting the transcription, translation and catalytic activity of major antioxidant enzymes. Since Hcys is an independent risk factor for many diseases, including cardiovascular and endocrine pathology, the study of the peculiarities of its metabolism is relevant.