Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

Abstract

The endothelium is a cellular monolayer that lines the inner surface of blood vessels and plays a central role in the maintenance of cardiovascular homeostasis by controlling platelet aggregation, vascular tone, blood fluidity and fibrinolysis, adhesion and transmigration of inflammatory cells, and angiogenesis. Endothelial dysfunctions are associated with various cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, and cardiovascular complications of diabetes. Numerous studies have established the antiinflammatory, anti-apoptotic, and anti-oxidant effects of hydrogen sulfide (H 2 S), the latest member to join the gasotransmitter family along with nitric oxide and carbon monoxide, on vascular endothelium. In addition, H 2 S may prime endothelial cells (ECs) toward angiogenesis and contribute to wound healing, aside to its well-known ability to relax vascular smooth muscle cells (VSMCs), thereby reducing blood pressure. Finally, H 2 S may inhibit VSMC proliferation and platelet aggregation. Consistently, a deficit in H 2 S homeostasis is involved in the pathogenesis of atherosclerosis and of hyperglycaemic endothelial injury. Therefore, the application of H 2 S-releasing drugs or using gene therapy to increase endogenous H 2 S level may help restore endothelial function and antagonize the progression of cardiovascular diseases. The present article reviews recent studies on the role of H 2 S in endothelial homeostasis, under both physiological and pathological conditions, and its putative therapeutic applications. Endothelial structure and functionThe endothelium lines the luminal surface of the entire vascular tree and the cardiac chambers, where it is termed endocardium. As a consequence, the endothelium presents a rather broad extension (300 to 1000 m 2 ) and weight (1.5 kg), achieving sizes comparable to other vital organs of the human body [1,2]. The endothelium can, therefore, be regarded as a real "organ spread across the organism" [3] and, as such, not only it is important for the regulation of local tissue functions, but also for maintaining the whole organism homeostasis [4]. Vascular endothelial cells (ECs) possess a polarized architecture: their luminal membrane is directly exposed to hematic constituents and circulating cells, while the basolateral surface is separated from surrounding tissues by a glycoprotein basement membrane -the sub-endothelial basement -which is formed by fibronectin, laminin, and collagen and is secreted by ECs themselves [2].Heterogeneity is, however, the hallmark of endothelium. ECs differ in morphology, function, and gene expression profile, so that even neighbouring cells from the same organ and blood vessel type exhibit distinct features [4]. For instance, vascular ECs may vary in size, shape, thickness and position of the nucleus. Albeit oriented along direction of blood flow, to attenuate the impact of shear stress forces on the vascular wall, microvascular ECs are rather thin (0.1 µm) and spindle-like, whilst their macrovascul...

Lower Hydrogen Sulfide Is Associated with Cardiovascular Mortality, Which Involves cPKCβII/Akt Pathway in Chronic Hemodialysis Patients

“…It is formed from L-cysteine by 2 pyridoxal-5 ′ -phosphate-dependent enzymes, cystathionine γ-lyase, cystathionine β-synthase and 3-mercatopyruvate sulfurtransferase [15] . The pathophysiologic functions of low H 2 S in cardiovascular system include increase of BP, endothelial dysfunction [16] and atherosclerosis formation [3,17] . The CSE/H 2 S pathway was also confirmed to participate in the development and progression of atherosclerosis in apolipoprotein E knock-out mice [18] .…”

The role of H2S bioavailability in endothelial dysfunction

“…The functional importance of the endothelium is realised by its wide coverage of the inner surface of the cardiovascular system, polarised architecture in blood vessels, and heterogeneity in its morphology, structure, and gene expression profile at different locations of different types of blood vessels [3]. …”

The coordination of S-sulfhydration, S-nitrosylation, and phosphorylation of endothelial nitric oxide synthase by hydrogen sulfide

“…Hydrogen sulfide (H 2 S) and nitric oxide (NO) are gasotransmitters involved in the homeostatic regulation of vascular functions (1)(2)(3). In vascular walls, endothelial nitric oxide synthase (eNOS) is the predominant NOS isoform for NO production, and cystathionine g-lyase (CSE) is mostly responsible for H 2 S production (1,2).…”