**4. Homocystein—factor of endothelial senescence and endothelial dysfunction**

In addition to cholesterol, the second important factor whose high blood concentration causes vascular endothelial damage is homocysteine. Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered an independent risk factor for atherosclerosis and cardiovascular disease, but the molecular basis of these compounds remains incompletely elucidated to date. There is a causal link, as studies have observed that impaired endothelial function, a key initial event in the development of atherosclerosis and CVD, is observed in hyperhomocysteinemia (HHcy). Various phenomena may explain the vascular toxicity associated with high homocysteine concentrations. For example, Hcy is an inhibitor of nitric oxide (NO) synthesis, a gaseous master regulator of endothelial homeostasis. In addition, Hcy is responsible for deregulating the signaling pathways associated with hydrogen sulphide another important endothelial gasotransmitter. Hcy is also involved in the loss of critical endothelial antioxidant systems and thus increases the intracellular concentration of reactive oxygen species (ROS) causing oxidative stress. ROS interfere with lipoprotein metabolism, forming oxidized forms of lipids that are removed by vascular wall macrophages contributing to the development of atherosclerotic vascular lesions. In addition, excess Hcy can be indirectly incorporated into proteins, a process referred to as N-homocysteinylation of proteins, inducing vascular damage. The inability to metabolize homocysteine and excess homocysteine decreases the synthesis of the universal methyl group donor, so necessary for epigenetic processes occurring in cells, and the hypomethylation of cellular DNA caused by the accumulation of S-adenosylhomocysteine (AdoHcy) also contributes to the molecular basis of Hcyinduced vascular toxicity and endothelial cell aging. A negative regulator of cellular methyltransferases, AdoHcy is a metabolic precursor of Hcy that accumulates under HHcy conditions [48].
