Homocysteine to hydrogen sulfide or hypertension

Abstract

Hyperhomocysteinemia, an increased level of plasma homocysteine, is an independent risk factor for the development of premature arterial fibrosis with peripheral and cerebro-vascular, neurogenic and hypertensive heart disease, coronary occlusion and myocardial infarction, as well as venous thromboembolism. It is reported that hyperhomocysteinemia causes vascular dysfunction by two major routes: (1) increasing blood pressure and, (2) impairing the vasorelaxation activity of endothelial-derived nitric oxide. The homocysteine activates metalloproteinases and induces collagen synthesis and causes imbalances of elastin/collagen ratio which compromise vascular elastance. The metabolites from hyperhomocysteinemic endothelium could modify components of the underlying muscle cells, leading to vascular dysfunction and hypertension. Homocysteine metabolizes in the body to produce H(2)S, which is a strong antioxidant and vasorelaxation factor. At an elevated level, homocysteine inactivates proteins by homocysteinylation including its endogenous metabolizing enzyme, cystathionine gamma-lyase. Thus, reduced production of H(2)S during hyperhomocysteinemia exemplifies hypertension and vascular diseases. In light of the present information, this review focuses on the mechanism of hyperhomocysteinemia-associated hypertension and highlights the novel modulatory role of H(2)S to ameliorate hypertension.

Fig. 1

Schematic of methionine metabolism and development of hyperhomocysteinemia. Homocysteine in the body further metabolizes to produce sulfate and excretes through kidney

Fig. 2

Schematic of homocysteine metabolism and formation of endogenous hydrogen sulfide (H₂S). CBS cystathionine β-synthase, CSE cystathionine γ-lyase, 3MST 3-mercaptopyruvate sulfurtransferase

Fig. 3

a Oxidation reduction and formation of nitrotyrosine by homocysteine. b Homocysteine causes reduction of thioredoxin and increases superoxide production by inducing NAD(P)H oxidase. Homocysteine also induces eNOS and iNOS to produce NO. Reaction of NO and tyrosine forms peroxynitrite and causes nitrosylation of protein tyrosine residues, such as actin and myosin. This leads to impairment of contractility and resulting in hypertension. H2S scavenges superoxide; therefore, reduces hypertension

Fig. 4

Homocysteine induces intracellular Ca²⁺ release and ECM production which results in vascular contraction and stiffness. H₂S helps faster release of intracellular calcium thereby prevents contractility and ECM formation

Fig. 5

Schematic of homocysteine-induced MMP activation, protein homocysteinylation and endothelial dysfunction that causes hypertension

Fig. 6

Schematic relationship of hyperhomocysteinemia, reduced H₂S and upregulation of angiotensin that may develop hypertension