Background and Purpose Hydrogen sulfide (H2S)‐releasing agents are viewed as potential antihypertensive drugs. Recently, natural isothiocyanates emerged as original H2S‐donor agents. Among them, erucin, present in some edible cruciferous plants, shows suitable H2S‐releasing properties and features of “druggability.” The aim of this work was to investigate the erucin‐mediated release of H2S inside vascular cells, its vasorelaxing effects, and activity on BP of normo and hypertensive animals. Experimental Approach Intracellular H2S‐release and the hyperpolarizing effect of erucin were tested using fluorescent dye, in human aortic smooth muscle cells (HASMCs). Its direct vasorelaxing effect and ability to inhibit noradrenaline‐induced vasoconstriction were evaluated on endothelium‐intact or ‐denuded rat aortic rings. Its vasodilator properties were tested in coronary arteries using Langendorff‐perfused rat hearts. Finally, erucin's antihypertensive activity was evaluated in vivo in normotensive and spontaneously hypertensive rats (SHRs) by recording systolic BP using the tail‐cuff method. Key Results Erucin induced the release of H2S inside HASMCs. Moreover, erucin hyperpolarized the membrane of HASMCs membrane in a concentration‐dependent manner. It induced vasodilatation of rat aortic rings, in endothelium‐denuded vessels. This effect was further improved by the presence of endothelial NO. When pre‐incubated with rat aortic rings, erucin induced concentration‐dependent inhibition of noradrenaline‐induced vasoconstriction. Erucin did not affect basal coronary flow but restored the flow to normal in pre‐contracted coronary vessels. Finally, in vivo, erucin decreased systolic BP in SHRs by about 25%, and restored the BP to values observed in normotensive rats. Conclusions and Implications Erucin is an H2S donor endowed with vasorelaxing and antihypertensive effects. Linked Articles This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

Background and Purpose Human malignant hyperthermia (MH) syndrome is induced by volatile anaesthetics and involves increased levels of cystathionine β‐synthase (CBS)‐derived H2S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. Kv7 channels, expressed in skeletal muscle, may be a molecular target for H2S. Here, we have investigated the role of Kv7 channels in MH. Experimental Approach Skeletal muscle biopsies were obtained from MH‐susceptible (MHS) and MH‐negative (MHN) patients. Immunohistochemistry, RT‐PCR, Western blot, and in vitro contracture test (IVCT) were carried out. Development and characterization of primary human skeletal muscle cells (PHSKMC) and evaluation of cell membrane potential were also performed. The persulfidation state of Kv7 channels and polysulfide levels were measured. Key Results Kv7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the Kv7 channel opener retigabine. Incubation of negative biopsies with NaHS, prior to retigabine addition, led to an MHS‐like positive response. MHS‐derived PHSKMC challenged with retigabine showed a paradoxical depolarizing effect, compared with the canonical hyperpolarizing effect. CBS expression and activity were increased in MHS biopsies, resulting in a major polysulfide bioavailability. Persulfidation of Kv7.4 channels was significantly higher in MHS than in MHN biopsies. Conclusions and Implications In skeletal muscle of MHS patients, CBS‐derived H2S induced persulfidation of Kv7 channels. This post‐translational modification switches the hyperpolarizing activity into depolarizing. This mechanism can contribute to the pathological skeletal muscle hypercontractility typical of MH syndrome. Linked Articles This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

Duchenne muscular dystrophy (DMD) is the most frequent X chromosome-linked disease caused by mutations in the gene encoding for dystrophin, leading to progressive and unstoppable degeneration of skeletal muscle tissues. Despite recent advances in the understanding of the molecular processes involved in the pathogenesis of DMD, there is still no cure. In this study, we aim at investigating the potential involvement of the transsulfuration pathway (TSP), and its by-end product namely hydrogen sulfide (H 2 S), in primary human myoblasts isolated from DMD donors and skeletal muscles of dystrophic ( mdx ) mice. In myoblasts of DMD donors, we demonstrate that the expression of key genes regulating the H 2 S production and TSP activity, including cystathionine γ lyase (CSE), cystathionine beta-synthase (CBS), 3 mercaptopyruvate sulfurtransferase (3-MST), cysteine dioxygenase (CDO), cysteine sulfonic acid decarboxylase (CSAD), glutathione synthase (GS) and γ -glutamylcysteine synthetase (γ-GCS) is reduced. Starting from these findings, using Nuclear Magnetic Resonance (NMR) and quantitative Polymerase Chain Reaction (qPCR) we show that the levels of TSP-related metabolites such as methionine, glycine, glutathione, glutamate and taurine, as well as the expression levels of the aforementioned TSP related genes, are significantly reduced in skeletal muscles of mdx mice compared to healthy controls, at both an early (7 weeks) and overt (17 weeks) stage of the disease. Importantly, the treatment with sodium hydrosulfide (NaHS), a commonly used H 2 S donor, fully recovers the impaired locomotor activity in both 7 and 17 old mdx mice. This is an effect attributable to the reduced expression of pro-inflammatory markers and restoration of autophagy in skeletal muscle tissues. In conclusion, our study uncovers a defective TSP pathway activity in DMD and highlights the role of H 2 S-donors for novel and safe adjuvant therapy to treat symptoms of DMD.

Disruption of sphingolipid homeostasis and signaling has been implicated in diabetes, cancer, cardiometabolic, and neurodegenerative disorders. Yet, mechanisms governing cellular sensing and regulation of sphingolipid homeostasis remain largely unknown. In yeast, serine palmitoyltransferase, catalyzing the first and rate‐limiting step of sphingolipid de novo biosynthesis, is negatively regulated by Orm1 and 2. Lowering sphingolipids triggers Orms phosphorylation, upregulation of serine palmitoyltransferase activity and sphingolipid de novo biosynthesis. However, mammalian orthologs ORMDLs lack the N‐terminus hosting the phosphosites. Thus, which sphingolipid(s) are sensed by the cells, and mechanisms of homeostasis remain largely unknown. Here, we identify sphingosine‐1‐phosphate (S1P) as key sphingolipid sensed by cells via S1PRs to maintain homeostasis. The increase in S1P‐S1PR signaling stabilizes ORMDLs, restraining SPT activity. Mechanistically, the hydroxylation of ORMDLs at Pro137 allows a constitutive degradation of ORMDLs via ubiquitin‐proteasome pathway, preserving SPT activity. Disrupting S1PR/ORMDL axis results in ceramide accrual, mitochondrial dysfunction, impaired signal transduction, all underlying endothelial dysfunction, early event in the onset of cardio‐ and cerebrovascular diseases. Our discovery may provide the molecular basis for therapeutic intervention restoring sphingolipid homeostasis.