Endothelial Dysfunction: The Link Between Homocysteine and Hydrogen Sulfide

Abstract

High level of homocysteine (hyperhomocysteinemia, HHcy) is associated with increased risk for vascular disease. Evidence for this emerges from epidemiological studies which show that HHcy is associated with premature peripheral, coronary artery and cerebrovascular disease independent of other risk factors. Possible mechanisms by which homocysteine causes vascular injury include endothelial injury, DNA dysfunction, proliferation of smooth muscle cells, increased oxidative stress, reduced activity of glutathione peroxidase and promoting inflammation. HHcy has been shown to cause direct damage to endothelial cells both in vitro and in vivo. Clinically, this manifests as impaired flow-mediated vasodilation and is mainly due to a reduction in nitric oxide synthesis and bioavailability. The effect of impaired nitric oxide release can in turn trigger and potentiate atherothrombogenesis and oxidative stress. Endothelial damage is a crucial aspect of atherosclerosis and precedes overt manifestation of disease. In addition, endothelial dysfunction is also associated with hypertension, diabetes, ischemia reperfusion injury and neurodegenerative diseases. Homocysteine is a precursor of hydrogen sulfide (H2S) which is formed by transulfuration process catalyzed by the enzymes, cystathionine β-synthase and cystathionine γ-lyase. H2S is a gasotransmitter that has emerged recently as a novel mediator in cardiovascular homeostasis. As a potent vasodilator, it plays several roles which include regulation of vessel diameter, protection of endothelium from redox stress, ischemia reperfusion injury and chronic inflammation. However, the precise mechanism by which it mediates these beneficial effects is complex and still remains unclear. Current evidence indicates H2S modulates cellular functions by a variety of intracellular signaling processes. In this review, we summarize the mechanisms of HHcy-induced endothelial dysfunction and the metabolism and physiological functions of H2S as a protective agent.

Phosphinodithioate and Phosphoramidodithioate Hydrogen Sulfide Donors

“…Al-Magableh and Hart (2011) and Hedegaard et al 2014)). As a result of these studies, H 2 S is often described as a "potent vasodilator" (Bhatia 2005;Pushpakumar et al 2014;Ariyaratnam et al 2013;Jang et al 2014;Baragatti et al 2013;Ghasemi et al 2012) despite data clearly showing otherwise. However, the addition of GYY4137 at concentrations and incubation times which deliver nM to low μM H 2 S also leads to vasodilation in vitro and in vivo (Table 1) suggesting blood vessels are acutely sensitive to small fluxes of H 2 S when it is generated in a manner and a level comparable to enzymatic (e.g.…”

Oxymatrine Inhibits Homocysteine-Mediated Autophagy via MIF/mTOR Signaling in Human Umbilical Vein Endothelial Cells

“…Among these, endothelial dysfunction is pivotal in the initiation and development of atherosclerosis [1, 2]. Homocysteine (Hcy)is an independent risk factor for atherosclerosis, and is thought to contribute to endothelial dysfunction through Hcy-induced cell injury [3]. The mechanism for Hcy-induced endothelial cell injury is not clear, but several studies have demonstrated that it involves autophagy [4].…”

Prevalence of Homocysteine‐Related Hypertension in Patients With Chronic Kidney Disease

“…Hcy is a sulfur-containing, nonprotein-forming amino acid synthesized from the normal biosynthesis of methionine and cysteine, and is an important intermediate in the one-carbon pathway. 25 We classified patients as having HHcy when Hcy levels exceeded the normal limit. The damaging effects of HHcy on endothelial function are, at least in part, through the inhibition of endothelial nitric oxide synthase, which produces endoplasmic reticulum stress.…”