Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function

Abstract

The goal of the present studies was to investigate the role of changes in hydrogen sulfide (H 2 S) homeostasis in the pathogenesis of hyperglycemic endothelial dysfunction. Exposure of bEnd3 microvascular endothelial cells to elevated extracellular glucose (in vitro "hyperglycemia") induced the mitochondrial formation of reactive oxygen species (ROS), which resulted in an increased consumption of endogenous and exogenous H 2 S. Replacement of H 2 S or overexpression of the H 2 S-producing enzyme cystathionine-γ-lyase (CSE) attenuated the hyperglycemia-induced enhancement of ROS formation, attenuated nuclear DNA injury, reduced the activation of the nuclear enzyme poly(ADP-ribose) polymerase, and improved cellular viability. In vitro hyperglycemia resulted in a switch from oxidative phosphorylation to glycolysis, an effect that was partially corrected by H 2 S supplementation. Exposure of isolated vascular rings to high glucose in vitro induced an impairment of endothelium-dependent relaxations, which was prevented by CSE overexpression or H 2 S supplementation. siRNA silencing of CSE exacerbated ROS production in hyperglycemic endothelial cells. Vascular rings from CSE −/− mice exhibited an accelerated impairment of endothelium-dependent relaxations in response to in vitro hyperglycemia, compared with wild-type controls. Streptozotocininduced diabetes in rats resulted in a decrease in the circulating level of H 2 S; replacement of H 2 S protected from the development of endothelial dysfunction ex vivo. In conclusion, endogenously produced H 2 S protects against the development of hyperglycemia-induced endothelial dysfunction. We hypothesize that, in hyperglycemic endothelial cells, mitochondrial ROS production and increased H 2 S catabolism form a positive feed-forward cycle. H 2 S replacement protects against these alterations, resulting in reduced ROS formation, improved endothelial metabolic state, and maintenance of normal endothelial function.

Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

“…These results have been corroborated by the finding that the circulating levels of H 2 S were lower in STZ-diabetic rats [178]. The same study shows that, under hyperglycaemic condition bEnd3, microvascular ECs accelerated H 2 S consumption due to the mitochondrial formation of ROS, which severely affected cell viability and caused nuclear DNA damage and switched cell metabolism from oxidative phosphorylation to glycolysis [178]. As expected, these features were associated to the impairment of endothelium-dependent relaxations of rat aortic rings exposed to high glucose in vitro.…”

“…H 2 S treatment or CSE over-expression protected ECs from the deleterious consequences of hyperglycaemia-induced enhancement of ROS formation and attenuated nuclear DNA injury [178]. H 2 S protected against the development of EC dysfunction in aortic tissues incubated in medium with elevated glucose concentration (in vitro "hyperglycemia") and reduced the bioenergetic derangements in ECs [178].…”

“…H 2 S protected against the development of EC dysfunction in aortic tissues incubated in medium with elevated glucose concentration (in vitro "hyperglycemia") and reduced the bioenergetic derangements in ECs [178]. On the other hand, CSE knockdown deteriorated hyperglycemia-induced ROS production and led to more severe loss of endothelium-dependent relaxant function [178]. Oxidative stress plays a major role in the development of diabetic microvascular complications [179].…”

Vitamin D Up-regulates Glucose Transporter 4 (GLUT4) Translocation and Glucose Utilization Mediated by Cystathionine-γ-lyase (CSE) Activation and H2S Formation in 3T3L1 Adipocytes

“…H 2 S is produced in vivo from L-cysteine by the action of two main enzymes, CSE and cystathionine ␤-synthase (5-7). Exogenous H 2 S supplementation reduces blood pressure, decreases atherosclerotic plaque size compared with those of controls in apolipoprotein E knock-out mice, and prevents progression of diabetic nephropathy in spontaneously hypertensive rats and endothelial dysfunction in diabetic rats (22,23). Several studies demonstrate that H 2 S is an antioxidant that regenerates GSH and lowers oxidative stress (5)(6)(7)11).…”

Highly sensitive sulphide mapping in live cells by kinetic spectral analysis of single Au-Ag core-shell nanoparticles

“…H 2 S equilibrates with aqueous sulphides (HS À and S 2 À ) in biological environments and has vital roles in various physiological and pathological processes, including vasorelaxation 5 , angiogenesis 6 , cerebral microcirculation 7 , neurotransmission 8,9 , inflammation 10 , apoptosis 11 , insulin signalling inhibition 12 , oxygen sensing 13 and energy production in mitochondria 14 . Meanwhile, the H 2 S levels are related to a number of diseases, such as Down syndrome 15 , Alzheimer disease 16 , hyperglycaemia 17 , ischaemia 18 and so on. To elucidate the complex behaviours of H 2 S in both healthy and disease states, it is crucial to measure H 2 S distribution in biological systems in real time.…”