Cystathionine γ-lyase regulates arteriogenesis through NO-dependent monocyte recruitment

AIMS: Hydrogen sulfide (H2S) is a vasoactive gasotransmitter that is endogenously produced in the vasculature by the enzyme cystathionine γ-lyase (CSE). However, the importance of CSE activity and local H2S generation for ischaemic vascular remodelling remains completely unknown. In this study, we examine the hypothesis that CSE critically regulates ischaemic vascular remodelling involving H2S-dependent mononuclear cell regulation of arteriogenesis. METHODS AND RESULTS: Arteriogenesis including mature vessel density, collateral formation, blood flow, and SPY angiographic blush rate were determined in wild-type (WT) and CSE knockout (KO) mice at different time points following femoral artery ligation (FAL). The role of endogenous H2S in regulation of IL-16 expression and subsequent recruitment of monocytes, and expression of VEGF and bFGF in ischaemic tissues, were determined along with endothelial progenitor cell (CD34/Flk1) formation and function. FAL of WT mice significantly increased CSE activity, expression and endogenous H2S generation in ischaemic tissues, and monocyte infiltration, which was absent in CSE-deficient mice. Treatment of CSE KO mice with the polysulfide donor diallyl trisulfide restored ischaemic vascular remodelling, monocyte infiltration, and cytokine expression. Importantly, exogenous H2S therapy restored nitric oxide (NO) bioavailability in CSE KO mice that was responsible for monocyte recruitment and arteriogenesis. CONCLUSION: Endogenous CSE/H2S regulates ischaemic vascular remodelling mediated during hind limb ischaemia through NO-dependent monocyte recruitment and cytokine induction revealing a previously unknown mechanism of arteriogenesis

Total sulfane sulfur bioavailability reflects ethnic and gender disparities in cardiovascular disease

Hydrogen sulfide (H2S) has emerged as an important physiological and pathophysiological signaling molecule in the cardiovascular system influencing vascular tone, cytoprotective responses, redox reactions, vascular adap- tation, and mitochondrial respiration. However, bioavailable levels of H2S in its various biochemical metabolite forms during clinical cardiovascular disease remain poorly understood. We performed a case-controlled study to quantify and compare the bioavailability of various biochemical forms of H2S in patients with and without cardiovascular disease (CVD). In our study, we used the reverse-phase high performance liquid chromatography monobromobimane assay to analytically measure bioavailable pools of H2S. Single nucleotide polymorphisms (SNPs) were also identified using DNA Pyrosequencing. We found that plasma acid labile sulfide levels were significantly reduced in Caucasian females with CVD compared with those without the disease. Conversely, plasma bound sulfane sulfur levels were significantly reduced in Caucasian males with CVD compared with those without the disease. Surprisingly, gender differences of H2S bioavailability were not observed in African Americans, although H2S bioavailability was significantly lower overall in this ethnic group compared to Caucasians. We also performed SNP analysis of H2S synthesizing enzymes and found a significant increase in cystathionine gamma-lyase (CTH) 1364 G-T allele frequency in patients with CVD compared to controls. Lastly, plasma H2S bioavailability was found to be predictive for cardiovascular disease in Caucasian subjects as de- termined by receiver operator characteristic analysis. These findings reveal that plasma H2S bioavailability could be considered a biomarker for CVD in an ethnic and gender manner. Cystathionine gamma-lyase 1346 G-T SNP might also contribute to the risk of cardiovascular disease development

Hydrogen sulfide and nitric oxide metabolites in the blood of free-ranging brown bears and their potential roles in hibernation

During winter hibernation, brown bears (Ursus arctos) lie in dens for half a year without eating while their basal metabolism is largely suppressed. To understand the underlying mechanisms of metabolic depression in hibernation, we measured type and content of blood metabolites of two ubiquitous inhibitors of mitochondrial respiration, hydrogen sulfide (H2S) and nitric oxide (NO), in winter-hibernating and summer-active free-ranging Scandinavian brown bears. We found that levels of sulfide metabolites were overall similar in summer-active and hibernating bears but their composition in the plasma differed significantly, with a decrease in bound sulfane sulfur in hibernation. High levels of unbound free sulfide correlated with high levels of cysteine (Cys) and with low levels of bound sulfane sulfur, indicating that during hibernation H2S, in addition to being formed enzymatically from the substrate Cys, may also be regenerated from its oxidation products, including thiosulfate and polysulfides. In the absence of any dietary intake, this shift in the mode of H2S synthesis would help preserve free Cys for synthesis of glutathione (GSH), a major antioxidant found at high levels in the red blood cells of hibernating bears. In contrast, circulating nitrite and erythrocytic S-nitrosation of glyceraldehyde-3-phosphate dehydrogenase, taken as markers of NO metabolism, did not change appreciably. Our findings reveal that remodeling of H2S metabolism and enhanced intracellular GSH levels are hallmarks of the aerobic metabolic suppression of hibernating bear

Sulfide Catabolism Ameliorates Hypoxic Brain Injury

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury

A tale of two gases: NO and H2S, foes or friends for life?

Nitric oxide (NO) and hydrogen sulfide (H2S) have emerged as dominant redox regulators of numerous aspects of cellular and physiological functions within several organ systems included cardiovascular, immune and neurological tissues. Recent studies have begun to reveal that these two gaseous molecules may have redundant or overlapping pathophysiological functions often involving similar molecular targets. However, it remains less clear when and how NO and H2S may interact under biological and disease processes. In this graphical review, we discuss the current understanding of NO and H2S interactions and how they may functionally influence each other and what this may mean for biology and mechanisms of disease

Effects of Embedded Helium on the Microstructure and Mechanical Properties of Erbium Films

A series of helium (He) charged nanograin-sized erbium (Er) films were deposited by direct current (DC)-magnetron sputtering with different He/Ar mixture gases. The microstructure and mechanical properties of He-charged Er films were investigated by X-ray diffraction (XRD), transmission electron microscopy (TEM), and nanoindentation. The helium concentrations in Er films, determined by elastic recoil detection analysis (ERDA), ranged from 0 to 49.6%, with the increase in He:Ar flow ratio up to 18:1. The XRD results show that the grain sizes of Er films decreased with and increase in He content. The embedded He atoms induced the formation of spherical nanometer He bubbles, and the diameter of the He bubbles increased with the He content. The hardness and Young’s modulus increased and decreased with the decreasing grain sizes of polycrystalline Er–He films. The mechanisms of mechanical properties with respect to the grain size and He content were discussed based on the Hall–Petch formula and composite spheres model

A Cuckoo Search Algorithm Using Improved Beta Distributing and Its Application in the Process of EDM

Lévy flights random walk is one of key parts in the cuckoo search (CS) algorithm to update individuals. The standard CS algorithm adopts the constant scale factor for this random walk. This paper proposed an improved beta distribution cuckoo search (IBCS) for this factor in the CS algorithm. In terms of local characteristics, the proposed algorithm makes the scale factor of the step size in Lévy flights showing beta distribution in the evolutionary process. In terms of the overall situation, the scale factor shows the exponential decay trend in the process. The proposed algorithm makes full use of the advantages of the two improvement strategies. The test results show that the proposed strategy is better than the standard CS algorithm or others improved by a single improvement strategy, such as improved CS (ICS) and beta distribution CS (BCS). For the six benchmark test functions of 30 dimensions, the average rankings of the CS, ICS, BCS, and IBCS algorithms are 3.67, 2.67, 1.5, and 1.17, respectively. For the six benchmark test functions of 50 dimensions, moreover, the average rankings of the CS, ICS, BCS, and IBCS algorithms are 2.83, 2.5, 1.67, and 1.0, respectively. Confirmed by our case study, the performance of the ABCS algorithm was better than that of standard CS, ICS or BCS algorithms in the process of EDM. For example, under the single-objective optimization convergence of MRR, the iteration number (13 iterations) of the CS algorithm for the input process parameters, such as discharge current, pulse-on time, pulse-off time, and servo voltage, was twice that (6 iterations) of the IBCS algorithm. Similar, the iteration number (17 iterations) of BCS algorithm for these parameters was twice that (8 iterations) of the IBCS algorithm under the single-objective optimization convergence of Ra. Therefore, it strengthens the CS algorithm’s accuracy and convergence speed

B4C-Al Composites Fabricated by the Powder Metallurgy Process

Due to the large thermal neutron absorption cross section of 10B, B4C-Al composites have been used as neutron absorbing materials in nuclear industries, which can offer not only good neutron shielding performance but also excellent mechanical properties. The distribution of B4C particles affects the mechanical performance and efficiency of the thermal neutron absorption of the composite materials. In this study, 15 wt % B4C-Al and 20 wt % B4C-Al composites were prepared using a powder metallurgy process, i.e., ball milling followed by pressing, sintering, hot-extrusion, and hot-rolling. The yield and tensile strengths of the composites were markedly increased with an increase in the milling energy and the percentages of B4C particles. Microstructure analysis and neutron radiography revealed that the high-energy ball milling induced the homogeneous distribution of B4C particles in the Al matrix and good bonding between the Al matrix and the B4C particles. The load transfer ability and mechanical properties of the composites were consequently improved. The results showed the high-energy ball milling process is an appropriate fabrication procedure to prevent the agglomeration of the reinforcement particles even if the matrix to reinforcement particle size ratio was nearly 10

Sulfide regulation of cardiovascular function in health and disease

Hydrogen sulfide (HS) has emerged as a gaseous signalling molecule with crucial implications for cardiovascular health. HS is involved in many biological functions, including interactions with nitric oxide, activation of molecular signalling cascades, post-translational modifications and redox regulation. Various preclinical and clinical studies have shown that HS and its synthesizing enzymes - cystathionine γ-lyase, cystathionine β-synthase and 3-mercaptosulfotransferase - can protect against cardiovascular pathologies, including arrhythmias, atherosclerosis, heart failure, myocardial infarction and ischaemia-reperfusion injury. The bioavailability of HS and its metabolites, such as hydropersulfides and polysulfides, is substantially reduced in cardiovascular disease and has been associated with single-nucleotide polymorphisms in HS synthesis enzymes. In this Review, we highlight the role of HS, its synthesizing enzymes and metabolites, their roles in the cardiovascular system, and their involvement in cardiovascular disease and associated pathologies. We also discuss the latest clinical findings from the field and outline areas for future study