Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H 2 S) is now receiving increasing attention. Here we show that H 2 S is physiologically generated by cystathionine γ-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H 2 S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H 2 S formation in response to vascular activation. These findings provide direct evidence that H 2 S is a physiologic vasodilator and regulator of blood pressure.Nitric oxide (NO) and carbon monoxide (CO) are established physiologic messenger molecules, and NO has an important role as an endothelial cell-derived relaxing factor (EDRF) and regulator of blood pressure (1,2). Indirect evidence has implicated another endogenous gasotransmitter, hydrogen sulfide (H 2 S), in similar functions (3-7). H 2 S can be produced by cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS) (3,4), but definitive evidence for either of these enzymes in the physiologic formation of H 2 S is lacking.To investigate the role of H 2 S as a physiologic vasorelaxant and determinant of blood pressure, we generated mice with a targeted deletion of the gene encoding CSE (8) (fig. S1, A to C). The homozygous (CSE −/− ) and heterozygous (CSE −/+ ) mutant mice were viable, fertile, and indistinguishable from their control wild-type littermates (CSE +/+ ) in terms of growth pattern.

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Hydrogen sulfide (H 2 S) has been traditionally known for its toxic effects on living organisms. The role of H 2 S in the homeostatic regulation of pancreatic insulin metabolism has been unclear. The present study is aimed at elucidating the effect of endogenously produced H 2 S on pancreatic insulin release and its role in diabetes development. Diabetes development in Zucker diabetic fatty (ZDF) rats was evaluated in comparison with Zucker fatty (ZF) and Zucker lean (ZL) rats. Pancreatic H 2 S production and insulin release were also assayed. It was found that H 2 S was generated in rat pancreas islets, catalyzed predominantly by cystathionine g-lyase (CSE). Pancreatic CSE expression and H 2 S production were greater in ZDF rats than in ZF or ZL rats. ZDF rats exhibited reduced serum insulin level, hyperglycemia, and insulin resistance. Inhibition of pancreatic H 2 S production in ZDF rats by intraperitoneal injection of DL-propargylglycine (PPG) for 4 weeks increased serum insulin level, lowered hyperglycemia, and reduced hemoglobin A1c level (Po0.05). Although in ZF rats it also reduced pancreatic H 2 S production and serum H 2 S level, PPG treatment did not alter serum insulin and glucose level. Finally, H 2 S significantly increased K ATP channel activity in freshly isolated rat pancreatic b-cells. It appears that insulin release is impaired in ZDF because of abnormally high pancreatic production of H 2 S. New therapeutic approach for diabetes management can be devised based on our observation by inhibiting endogenous H 2 S production from pancreas. KEYWORDS: diabetes; hydrogen sulfide; insulin release; K ATP channel; pancreas; type 2 diabetes mellitus Known as a swamp gas or 'rotten egg' gas, hydrogen sulfide (H 2 S) has yielded a public image of air pollutant for centuries. Physiological importance of H 2 S as a gasotransmitter has been realized for less than a decade. Endogenous production of H 2 S from L-cysteine is catalyzed by cystathionine b-synthase (CBS) and/or cystathionine g-lyase (CSE) with ammonium and pyruvate as co-products. 1 This process occurs in different organs and tissues, such as neuronal, vascular, and intestinal tissues. 2 Physiological concentrations of circulating H 2 S have been reported in the range of 45-300 mM. 1 At this physiological range, exogenous H 2 S has been shown to relax different vascular tissues, including isolated rat aortae and perfused mesenteric artery bed. 3-5 Altered cell proliferation or apoptosis induced by H 2 S has also been widely reported. [6][7][8][9][10] Endogenous production and physiological function of H 2 S in pancreas have been studied with identification of both CBS and CSE in rat pancreatic tissues or cloned rat pancreatic b-cell line. 11,12 In recent years, pathophysiological implications of the CSE/H 2 S system in diabetes have been reported. 12 CSE mRNA expression and H 2 S formation in rat pancreas was significantly increased after diabetes induction by streptozotocin injection. 12 CBS expression was reported in pancreatic acinar cells. 13 Y...

Cystathionine ␥-lyase (CSE) is a key enzyme in the transsulfuration pathway, which uses L-cysteine to produce hydrogen sulfide (H 2 S). Functional changes of pancreatic beta cells induced by endogenous H 2 S have been reported, but the effect of the CSE/H 2 S system on pancreatic beta cell survival has not been known. In this study, we demonstrate that H 2 S at physiologically relevant concentrations induced apoptosis of INS-1E cells, an insulin-secreting beta cell line. Transfection of INS-1E cells with a recombinant defective adenovirus containing the CSE gene (Ad-CSE) resulted in a significant increase in CSE expression and H 2 S production. Ad-CSE transfection also stimulated apoptosis. The other two end products of CSE-catalyzed enzymatic reaction, ammonium and pyruvate, had no effects on INS-1E cell apoptosis, indicating that overexpression of CSE may stimulate INS-1E cell apoptosis via increased endogenous production of H 2 S. Both exogenous H 2 S (100 M) and Ad-CSE transfection inhibited ERK1/2 but activated p38 MAPK. Interestingly, BiP and CHOP, two indicators of endoplasmic reticulum (ER) stress, were up-regulated in H 2 S-and CSE-mediated apoptosis in INS-1E cells. After suppressing CHOP mRNA expression, H 2 S-induced apoptosis of INS-1E cells was significantly decreased. Inhibition of p38 MAPK, but not of ERK1/2, inhibited the expression of BiP and CHOP and decreased H 2 S-stimulated apoptosis, suggesting that p38 MAPK activation functions upstream of ER stress to initiate H 2 S-induced apoptosis. It is concluded that H 2 S induces apoptosis of insulin-secreting beta cells by enhancing ER stress via p38 MAPK activation. Our findings may help unmask a novel role of CSE/H 2 S system in regulating pancreatic functions under physiological condition and in diabetes.Cystathionine ␥-lyase (CSE, 5 EC 4.4.1.1) is a key pyridoxal 5Ј-phosphate-dependent enzyme in the trans-sulfuration pathway, which uses L-cysteine to produce hydrogen sulfide (H 2 S), a novel and important gasotransmitter (1-3). Endogenous productions of H 2 S in different organs and tissues as well as the circulatory concentration of H 2 S have been elucidated, and the physiological importance of H 2 S has gained increasing recognition (2-5).Diabetes is a spectrum of clinical conditions arising from relative or absolute insulin deficiency with decreased functional beta cell mass (6). Any change in beta cell mass must reflect an imbalance between proliferation (neogenesis or replication) and cell death (necrosis or apoptosis) (7). Excessive loss of beta cells constitutes one of the causes of diabetes, and apoptosis is considered to be the main mode of beta cell death in type I and type II diabetes (8). In recent years, pathophysiological implications of the CSE/H 2 S system in diabetes have been reported (9, 10). Endogenous production of H 2 S together with the expression of CSE and cystathionine ␤-synthase (CBS), another H 2 S-producing enzyme, was identified in rat pancreatic tissues (9, 10). CSE mRNA expression and H 2 S formation in the rat...

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Endogenous hydrogen sulfide (H 2 S), generated from homocysteine metabolism mainly catalyzed by cystathionine ␥-lyase (CSE), possesses important functions in the cardiovascular system. In this study, we investigated the role of H 2 S during the pathogenesis of neointimal formation induced by balloon injury in rats. CSE mRNA levels were reduced by 86.5% at 1 week and 64.0% at 4 weeks after balloon injury compared with the uninjured controls. CSE activity was also correspondingly reduced. Endogenous production of H 2 S in the injured carotid artery was significantly inhibited at 1 week and 4 weeks after balloon injury. Treatment with NaHS (a donor of H 2 S) enhanced methacholine-induced vasorelaxation of balloon-injured artery. More importantly, treatment with NaHS significantly inhibited neointima formation (0.15 ؎ 0.01 mm 2 versus 0.21 ؎ 0.01 mm 2 , P < 0.001) of the balloon-injured carotid arteries and reduced the intima/media ratio (1.05 ؎ 0.07 versus 1.43 ؎ 0.06, P < 0.001). A significant decrease in vascular smooth muscle cell proliferation was demonstrated by bromodeoxyuridine incorporation at day 7 after injury. In conclusion, CSE expression and H 2 S production are reduced during the development of balloon injury-induced neointimal hyperplasia, and treatment with NaHS significantly reduces neointimal lesion formation.

Aqueous Zn-ion batteries have aroused much attention recently, yet challenges still exist in the lack of low-cost, highly stable electrolytes to tackle the serious side reactions at Zn anode-electrolyte interface. Herein, a ZnSO 4based low-cost aqueous electrolyte is demonstrated with a small amount of eco-friendly silk peptide as an efficient additive. Compared with silk sericin and fibroin, silk peptide with abundant strong polar groups (COOH and NH 2 ) suppresses the side reactions. Namely, silk peptide regulates the solvation structure of Zn 2+ to decrease coordinated active H 2 O and SO 4 2− , and tends to anchor on Zn anode surface for the isolation of contact H 2 O/SO 4 2− as well as electrostatic shielding, demonstrating synergistic solvation and interface regulating effect. Consequently, the excellent cycle life (3000 h) and Coulombic efficiency (99.7%) of Zn anodes are revealed in 2 m ZnSO 4 electrolyte with only 5 mg mL −1 of silk peptide (≈0.49 USD L −1 ), promising practical applications of reversible zinc-ion batteries.