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1
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Liu T, Zhang M, Hanson S, Juarez R, Wilson S, Schroeder H, Li Q, Zhu L, Zhang G, Blood AB. H 2S Increases Blood Pressure via Activation of L-Type Calcium Channels with Mediation by HS • Generated from Reactions with Oxyhemoglobin. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305866. [PMID: 38685626 PMCID: PMC11234399 DOI: 10.1002/advs.202305866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 03/04/2024] [Indexed: 05/02/2024]
Abstract
Although the gasotransmitter hydrogen sulfide (H2S) is well known for its vasodilatory effects, H2S also exhibits vasoconstricting properties. Herein, it is demonstrated that administration of H2S as intravenous sodium sulfide (Na2S) increased blood pressure in sheep and rats, and this effect persisted after H2S has disappeared from the blood. Inhibition of the L-type calcium channel (LTCC) diminished the hypertensive effects. Incubation of Na2S with whole blood, red blood cells, methemoglobin, or oxyhemoglobin produced a hypertensive product of H2S, which is not hydrogen thioperoxide, metHb-SH- complexes, per-/poly- sulfides, or thiolsulfate, but rather a labile intermediate. One-electron oxidation of H2S by oxyhemoglobin generated its redox cousin, sulfhydryl radical (HS•). Consistent with the role of HS• as the hypertensive intermediate, scavenging HS• inhibited Na2S-induced vasoconstriction and activation of LTCCs. In conclusion, H2S causes vasoconstriction that is dependent on the activation of LTCCs and generation of HS• by oxyhemoglobin.
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Affiliation(s)
- Taiming Liu
- Division of NeonatologyDepartment of PediatricsLoma Linda University School of MedicineLoma LindaCA92354USA
| | - Meijuan Zhang
- Division of NeonatologyDepartment of PediatricsLoma Linda University School of MedicineLoma LindaCA92354USA
| | - Shawn Hanson
- Lawrence D. Longo Center for Perinatal BiologyLoma Linda University School of MedicineLoma LindaCA92354USA
| | - Rucha Juarez
- Lawrence D. Longo Center for Perinatal BiologyLoma Linda University School of MedicineLoma LindaCA92354USA
| | - Sean Wilson
- Lawrence D. Longo Center for Perinatal BiologyLoma Linda University School of MedicineLoma LindaCA92354USA
| | - Hobe Schroeder
- Lawrence D. Longo Center for Perinatal BiologyLoma Linda University School of MedicineLoma LindaCA92354USA
| | - Qian Li
- Department of MedicineGregory Fleming James Cystic Fibrosis Research CenterUniversity of Alabama at BirminghamBirminghamAL35294UK
| | - Lingchao Zhu
- Department of ChemistryUniversity of CaliforniaRiversideCA92521USA
| | - Guangyu Zhang
- Mass spectrometry core facilityLoma Linda UniversityLoma LindaCA92354USA
| | - Arlin B. Blood
- Division of NeonatologyDepartment of PediatricsLoma Linda University School of MedicineLoma LindaCA92354USA
- Lawrence D. Longo Center for Perinatal BiologyLoma Linda University School of MedicineLoma LindaCA92354USA
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2
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Herrald AL, Ambrogi EK, Mirica KA. Electrochemical Detection of Gasotransmitters: Status and Roadmap. ACS Sens 2024; 9:1682-1705. [PMID: 38593007 PMCID: PMC11196117 DOI: 10.1021/acssensors.3c02529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), are a class of gaseous, endogenous signaling molecules that interact with one another in the regulation of critical cardiovascular, immune, and neurological processes. The development of analytical sensing mechanisms for gasotransmitters, especially multianalyte mechanisms, holds vast importance and constitutes a growing area of study. This review provides an overview of electrochemical sensing mechanisms with an emphasis on opportunities in multianalyte sensing. Electrochemical methods demonstrate good sensitivity, adequate selectivity, and the most well-developed potential for the multianalyte detection of gasotransmitters. Future research will likely address challenges with sensor stability and biocompatibility (i.e., sensor lifetime and cytotoxicity), sensor miniaturization, and multianalyte detection in biological settings.
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Affiliation(s)
- Audrey L Herrald
- Department of Chemistry, Burke Laboratory, Dartmouth College, 41 College Street, Hanover, New Hampshire 03755, United States
| | - Emma K Ambrogi
- Department of Chemistry, Burke Laboratory, Dartmouth College, 41 College Street, Hanover, New Hampshire 03755, United States
| | - Katherine A Mirica
- Department of Chemistry, Burke Laboratory, Dartmouth College, 41 College Street, Hanover, New Hampshire 03755, United States
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3
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Kumar M. Hydrogen sulfide: From a toxic gas to a potential therapy for COVID-19 and inflammatory disorders. Nitric Oxide 2023; 140-141:8-15. [PMID: 37648016 DOI: 10.1016/j.niox.2023.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/06/2023] [Accepted: 08/26/2023] [Indexed: 09/01/2023]
Abstract
COVID-19 has been shown to induce inflammatory disorders and CNS manifestations. Swift and efficient treatment strategies are urgently warranted for the management of COVID, inflammatory and neurological disorders. Hydrogen sulfide (H2S) has been associated with several clinical disorders due to its potential to influence a broad range of biological signalling pathways. According to recent clinical studies, COVID patients with lower physiological H2S had higher fatality rates. These findings clearly demonstrate an inverse correlation between H2S levels and the severity of COVID-19. H2S has been proposed as a protective molecule because of its antioxidant, anti-inflammatory, and antiviral properties. Various H2S-releasing prodrugs, hybrids and natural compounds have been tested for their therapeutic efficacy in viral infections and inflammatory disorders. In this review, I am highlighting the rationale for using H2S-based interventions for the management of COVID-19 and post-infection inflammatory disorders including neuroinflammation. I am also proposing therepurposing of existing H2S-releasing prodrugs, developing new NO-H2S-hybrids, targeting H2S metabolic pathways, and using H2S-producing dietary supplements as viable defensive strategies against SARS-CoV-2 infection and COVID-19 pathologies.
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Affiliation(s)
- Mohit Kumar
- Centre for Excellence in Functional Foods, Food and Nutrition Biotechnology Division, National Agri-Food Biotechnology Institute, S.A.S Nagar, Punjab, 140306, India.
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4
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Rodkin S, Nwosu C, Sannikov A, Raevskaya M, Tushev A, Vasilieva I, Gasanov M. The Role of Hydrogen Sulfide in Regulation of Cell Death following Neurotrauma and Related Neurodegenerative and Psychiatric Diseases. Int J Mol Sci 2023; 24:10742. [PMID: 37445920 DOI: 10.3390/ijms241310742] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/15/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Injuries of the central (CNS) and peripheral nervous system (PNS) are a serious problem of the modern healthcare system. The situation is complicated by the lack of clinically effective neuroprotective drugs that can protect damaged neurons and glial cells from death. In addition, people who have undergone neurotrauma often develop mental disorders and neurodegenerative diseases that worsen the quality of life up to severe disability and death. Hydrogen sulfide (H2S) is a gaseous signaling molecule that performs various cellular functions in normal and pathological conditions. However, the role of H2S in neurotrauma and mental disorders remains unexplored and sometimes controversial. In this large-scale review study, we examined the various biological effects of H2S associated with survival and cell death in trauma to the brain, spinal cord, and PNS, and the signaling mechanisms underlying the pathogenesis of mental illnesses, such as cognitive impairment, encephalopathy, depression and anxiety disorders, epilepsy and chronic pain. We also studied the role of H2S in the pathogenesis of neurodegenerative diseases: Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, we reviewed the current state of the art study of H2S donors as neuroprotectors and the possibility of their therapeutic uses in medicine. Our study showed that H2S has great neuroprotective potential. H2S reduces oxidative stress, lipid peroxidation, and neuroinflammation; inhibits processes associated with apoptosis, autophagy, ferroptosis and pyroptosis; prevents the destruction of the blood-brain barrier; increases the expression of neurotrophic factors; and models the activity of Ca2+ channels in neurotrauma. In addition, H2S activates neuroprotective signaling pathways in psychiatric and neurodegenerative diseases. However, high levels of H2S can cause cytotoxic effects. Thus, the development of H2S-associated neuroprotectors seems to be especially relevant. However, so far, all H2S modulators are at the stage of preclinical trials. Nevertheless, many of them show a high neuroprotective effect in various animal models of neurotrauma and related disorders. Despite the fact that our review is very extensive and detailed, it is well structured right down to the conclusions, which will allow researchers to quickly find the proper information they are interested in.
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Affiliation(s)
- Stanislav Rodkin
- Department of Bioengineering, Faculty of Bioengineering and Veterinary Medicine, Don State Technical University, 344000 Rostov-on-Don, Russia
| | - Chizaram Nwosu
- Department of Bioengineering, Faculty of Bioengineering and Veterinary Medicine, Don State Technical University, 344000 Rostov-on-Don, Russia
| | - Alexander Sannikov
- Department of Psychiatry, Rostov State Medical University, 344022 Rostov-on-Don, Russia
| | - Margarita Raevskaya
- Department of Bioengineering, Faculty of Bioengineering and Veterinary Medicine, Don State Technical University, 344000 Rostov-on-Don, Russia
| | - Alexander Tushev
- Neurosurgical Department, Rostov State Medical University Clinic, 344022 Rostov-on-Don, Russia
| | - Inna Vasilieva
- N.V. Sklifosovsky Institute of Clinical Medicine, Department of Polyclinic Therapy, I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia
| | - Mitkhat Gasanov
- Department of Internal Diseases #1, Rostov State Medical University, 344022 Rostov-on-Don, Russia
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5
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Trummer M, Galardon E, Mayer B, Steiner G, Stamm T, Kloesch B. Polysulfides derived from the hydrogen sulfide and persulfide donor P* inhibit IL-1β-mediated inducible nitric oxide synthase signaling in ATDC5 cells: are CCAAT/enhancer-binding proteins β and δ involved in the anti-inflammatory effects of hydrogen sulfide and polysulfides? Nitric Oxide 2022; 129:41-52. [DOI: 10.1016/j.niox.2022.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 09/14/2022] [Accepted: 09/27/2022] [Indexed: 11/05/2022]
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6
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Oza PP, Kashfi K. Utility of NO and H 2S donating platforms in managing COVID-19: Rationale and promise. Nitric Oxide 2022; 128:72-102. [PMID: 36029975 PMCID: PMC9398942 DOI: 10.1016/j.niox.2022.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/01/2022] [Accepted: 08/10/2022] [Indexed: 01/08/2023]
Abstract
Viral infections are a continuing global burden on the human population, underscored by the ramifications of the COVID-19 pandemic. Current treatment options and supportive therapies for many viral infections are relatively limited, indicating a need for alternative therapeutic approaches. Virus-induced damage occurs through direct infection of host cells and inflammation-related changes. Severe cases of certain viral infections, including COVID-19, can lead to a hyperinflammatory response termed cytokine storm, resulting in extensive endothelial damage, thrombosis, respiratory failure, and death. Therapies targeting these complications are crucial in addition to antiviral therapies. Nitric oxide and hydrogen sulfide are two endogenous gasotransmitters that have emerged as key signaling molecules with a broad range of antiviral actions in addition to having anti-inflammatory properties and protective functions in the vasculature and respiratory system. The enhancement of endogenous nitric oxide and hydrogen sulfide levels thus holds promise for managing both early-stage and later-stage viral infections, including SARS-CoV-2. Using SARS-CoV-2 as a model for similar viral infections, here we explore the current evidence regarding nitric oxide and hydrogen sulfide's use to limit viral infection, resolve inflammation, and reduce vascular and pulmonary damage.
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Affiliation(s)
- Palak P Oza
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, 10091, USA.
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7
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Kang Y, Kim JS, Cui H, Jang MJ, Zhang YH, Hwang HY. Comparative analysis of the hydrogen sulphide pathway in internal thoracic artery and radial artery. Interact Cardiovasc Thorac Surg 2022; 35:6569085. [PMID: 35426918 PMCID: PMC9631973 DOI: 10.1093/icvts/ivac105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 04/14/2022] [Indexed: 11/12/2022] Open
Affiliation(s)
- Yoonjin Kang
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital , Seoul, Republic of Korea
| | - Jun Sung Kim
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine , Seongnam, Republic of Korea
| | - Huixing Cui
- Department of Physiology, College of Medicine, Seoul National University , Seoul, Republic of Korea
| | - Myoung-Jin Jang
- Medical Research Collaborating Center, Seoul National University Hospital, Seoul National College of Medicine , Seoul, Republic of Korea
| | - Yin Hua Zhang
- Department of Physiology, College of Medicine, Seoul National University , Seoul, Republic of Korea
| | - Ho Young Hwang
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital , Seoul, Republic of Korea
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8
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Ranjana M, Sunil D. Naphthalimide derivatives as fluorescent probes for imaging endogenous gasotransmitters. Chem Biol Interact 2022; 363:110022. [PMID: 35753358 DOI: 10.1016/j.cbi.2022.110022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/07/2022] [Accepted: 06/17/2022] [Indexed: 11/03/2022]
Abstract
Gasotransmitters have gained significant recognition attributed to their evident biological impacts, and is accepted as a promising and less-explored area with immense research scope. The three-member family comprising of nitric oxide, carbon monoxide and hydrogen sulphide as endogenous gaseous signaling molecules have been found to elicit a plethora of crucial biological functions, spawning a new research area. The sensing of these small molecules is vital to gain deeper insights into their functions, as they can act both as a friend or a foe in mammalian systems. The initial sections of the review present the physiological and pathophysiological roles of these endogenous gas transmitters and their synergistic interactions. Further, various detection approaches, especially the usage of fascinating features of 1,8-naphthalimide as fluorescent probe in the detection and monitoring of these small signaling molecules are highlighted. The current limitations and the future scope of improving the sensing of the three gasotransmitters are also discussed.
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Affiliation(s)
- M Ranjana
- Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576 104, Karnataka, India
| | - Dhanya Sunil
- Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576 104, Karnataka, India.
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9
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Pinto RV, Carvalho S, Antunes F, Pires J, Pinto ML. Emerging Nitric Oxide and Hydrogen Sulfide Releasing Carriers for Skin Wound Healing Therapy. ChemMedChem 2021; 17:e202100429. [PMID: 34714595 DOI: 10.1002/cmdc.202100429] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/26/2021] [Indexed: 12/19/2022]
Abstract
Nitric oxide (NO) and hydrogen sulfide (H2 S) have been recognized as important signalling molecules involved in multiple physiological functions, including wound healing. Their exogenous delivery has been established as a new route for therapies, being the topical application the nearest to commercialization. Nevertheless, the gaseous nature of these therapeutic agents and their toxicity at high levels imply additional challenges in the design of effective delivery systems, including the tailoring of their morphology and surface chemistry to get controllable release kinetics and suitable lifetimes. This review highlights the increasing interest in the use of these gases in wound healing applications by presenting the various potential strategies in which NO and/or H2 S are the main therapeutic agents, with focus on their conceptual design, release behaviour and therapeutic performance. These strategies comprise the application of several types of nanoparticles, polymers, porous materials, and composites as new releasing carriers of NO and H2 S, with characteristics that will facilitate the application of these molecules in the clinical practice.
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Affiliation(s)
- Rosana V Pinto
- CERENA-Centro de Recursos Naturais e Ambiente, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001, Lisboa, Portugal.,CQE-Ciências-Centro de Química Estrutural, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 16, 1749-016, Lisboa, Portugal
| | - Sílvia Carvalho
- CERENA-Centro de Recursos Naturais e Ambiente, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001, Lisboa, Portugal.,CQE-Ciências-Centro de Química Estrutural, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 16, 1749-016, Lisboa, Portugal
| | - Fernando Antunes
- CQE-Ciências-Centro de Química Estrutural, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 16, 1749-016, Lisboa, Portugal
| | - João Pires
- CQE-Ciências-Centro de Química Estrutural, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 16, 1749-016, Lisboa, Portugal
| | - Moisés L Pinto
- CERENA-Centro de Recursos Naturais e Ambiente, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001, Lisboa, Portugal
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10
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Abdel-Zaher AO, Abd-Ellatief RB, Aboulhagag NA, Farghaly HSM, Al-Wasei FMM. The potential relationship between gasotransmitters and oxidative stress, inflammation and apoptosis in lead-induced hepatotoxicity in rats. Tissue Cell 2021; 71:101511. [PMID: 33725649 DOI: 10.1016/j.tice.2021.101511] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/11/2021] [Accepted: 02/11/2021] [Indexed: 12/30/2022]
Abstract
The interrelationship between gasotransmitters and oxidative stress, inflammation and apoptosis in lead-induced hepatotoxicity was investigated in this study. On prolonged exposure, lead was accumulated in liver tissue of rats and impaired liver function and structure as assessed by measurement of the serum hepatic function markers and by histopathological examination. The accumulated metal induced oxidative stress, inflammation and apoptosis in the liver. Also, it increased nitric oxide (NO) production and decreased hydrogen sulfide (H2S) level and heme oxygenase (HO-1) concentration in liver tissue. Decreasing of NO production by L-N(G)-nitroarginine methyl ester (L-NAME) and increasing of H2S level by sodium hydrosulfide (NaHS) and carbon monoxide (CO) level by carbon monoxide-releasing molecule-A1 (CORM-A1) inhibited lead-induced impairment of liver function and structure. Concomitantly, these agents inhibited lead intoxication-induced oxidative stress, inflammation, apoptosis, nitrosative stress and reduction of HO-1 concentration and H2S level. Furthermore, concurrent treatment with these agents inhibited lead intoxication-induced increase in the protein expressions of inducible NO synthase, tumor necrosis factor-alpha, interleukin-1beta and caspase-3 as well as decrease in protein expressions of HO-1 and cystathionine-γ-lyase in the liver. NO donor, l-arginine and H2S and CO biosynthesis inhibitors, trifluoro-DL-alanine and zinc deutroporphyrin, respectively aggravated the toxic effects of lead. These results indicate, for the first time, that there is an interrelationship between gasotransmitters and lead-induced hepatotoxicity. The ability of L-N AME, NaHS and CORM-A1 to provide protective effects against lead-induced hepatotoxicity may positively correlate, to their ability to suppress hepatic oxidative stress, nitrosative stress, inflammation and apoptosis.
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Affiliation(s)
- Ahmed O Abdel-Zaher
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | - Rasha B Abd-Ellatief
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Noha A Aboulhagag
- Department of Patholology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Hanan S M Farghaly
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Fahmy M M Al-Wasei
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
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11
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Fuschillo S, Palomba L, Capparelli R, Motta A, Maniscalco M. Nitric Oxide and Hydrogen Sulfide: A Nice Pair in the Respiratory System. Curr Med Chem 2020; 27:7136-7148. [DOI: 10.2174/0929867327666200310120550] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 01/25/2020] [Accepted: 02/05/2020] [Indexed: 01/15/2023]
Abstract
Nitric Oxide (NO) is internationally regarded as a signal molecule involved in several
functions in the respiratory tract under physiological and pathogenic conditions. Hydrogen Sulfide
(H2S) has also recently been recognized as a new gasotransmitter with a diverse range of functions
similar to those of NO.
Depending on their respective concentrations, both these molecules act synergistically or antagonistically
as signals or damage promoters. Nevertheless, available evidence shows that the complex
biological connections between NO and H2S involve multiple pathways and depend on the site of
action in the respiratory tract, as well as on experimental conditions. This review will provide an
update on these two gasotransmitters in physiological and pathological processes.
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Affiliation(s)
- Salvatore Fuschillo
- Istituti Clinici Scientifici Maugeri IRCCS, Pulmonary Rehabilitation Division of the Telese Terme Institute, 82037 Telese Terme (BN), Italy
| | - Letizia Palomba
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino (PU), Italy
| | - Rosanna Capparelli
- Department of Agriculture, University of Naples “Federico II”, 80055 Portici, (NA), Italy
| | - Andrea Motta
- Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli (NA), Italy
| | - Mauro Maniscalco
- Istituti Clinici Scientifici Maugeri IRCCS, Pulmonary Rehabilitation Division of the Telese Terme Institute, 82037 Telese Terme (BN), Italy
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12
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Dillon KM, Carrazzone RJ, Matson JB, Kashfi K. The evolving landscape for cellular nitric oxide and hydrogen sulfide delivery systems: A new era of customized medications. Biochem Pharmacol 2020; 176:113931. [PMID: 32224139 PMCID: PMC7263970 DOI: 10.1016/j.bcp.2020.113931] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 03/20/2020] [Indexed: 02/09/2023]
Abstract
Nitric oxide (NO) and hydrogen sulfide (H2S) are industrial toxins or pollutants; however, both are produced endogenously and have important biological roles in most mammalian tissues. The recognition that these gasotransmitters have a role in physiological and pathophysiological processes has presented opportunities to harness their intracellular effects either through inhibition of their production; or more commonly, through inducing their levels and or delivering them by various modalities. In this review article, we have focused on an array of NO and H2S donors, their hybrids with other established classes of drugs, and the various engineered delivery platforms such a fibers, polymers, nanoparticles, hydrogels, and others. In each case, we have reviewed the rationale for their development.
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Affiliation(s)
- Kearsley M Dillon
- Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA 24061, USA; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA
| | - Ryan J Carrazzone
- Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA 24061, USA; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA
| | - John B Matson
- Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA 24061, USA; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, 160 Convent Avenue, New York, NY 10031, USA; Graduate Program in Biology, City University of New York Graduate Center, NY, USA.
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13
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Li H, Liu S, Wang Z, Zhang Y, Wang K. Hydrogen sulfide attenuates diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor. Exp Biol Med (Maywood) 2020; 245:823-834. [PMID: 32268802 DOI: 10.1177/1535370220918193] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
IMPACT STATEMENT There are currently approximately 425 million diabetic patients worldwide, of which approximately 90% of patients with diabetes suffer from neuropathy. Diabetic neuropathic pain (DNP) is a common complication of diabetic neuropathy. Nearly half of the patients hospitalized with diabetes have pain symptoms or symptoms related to neurological injury, and the incidence increases with age and diabetic duration. Anti-DNP analgesics have either limited therapeutic effects or serious side effects or lack of clinical trials, which has limited their application. Physiopathological mechanisms and treatment of DNP remain a significant challenge. The present confirmed that inhalation of H2S may attenuate the diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor. It provides us the animal study foundation for the application of H2S on the treatment of DNP and clarifies some target molecules in the pain modulation of DNP.
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Affiliation(s)
- Hao Li
- Medical Management Department, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong 250117, China
| | - Shulin Liu
- Department of Aviation Medicine, Naval Medical Institute, Second Military Medical University, Shanghai 200433, China
| | - Zheng Wang
- Pre Hospital Emergency Department, Shandong Otolaryngology Hospital Affiliated to Shandong University (West Hospital of Shandong Provincial Hospital), Shandong 250117, China
| | - Yonglai Zhang
- Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong 250117, China
| | - Kaiguo Wang
- Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong 250117, China
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14
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Gheibi S, Samsonov AP, Gheibi S, Vazquez AB, Kashfi K. Regulation of carbohydrate metabolism by nitric oxide and hydrogen sulfide: Implications in diabetes. Biochem Pharmacol 2020; 176:113819. [PMID: 31972170 DOI: 10.1016/j.bcp.2020.113819] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 01/15/2020] [Indexed: 12/19/2022]
Abstract
Nitric oxide (NO) and hydrogen sulfide (H2S) are two gasotransmitters that are produced in the human body and have a key role in many of the physiological activities of the various organ systems. Decreased NO bioavailability and deficiency of H2S are involved in the pathophysiology of type 2 diabetes and its complications. Restoration of NO levels have favorable metabolic effects in diabetes. The role of H2S in pathophysiology of diabetes is however controversial; H2S production is decreased during development of obesity, diabetes, and its complications, suggesting the potential therapeutic effects of H2S. On the other hand, increased H2S levels disturb the pancreatic β-cell function and decrease insulin secretion. In addition, there appear to be important interactions between NO and H2S at the levels of both biosynthesis and signaling pathways, yet clear an insight into this relationship is lacking. H2S potentiates the effects of NO in the cardiovascular system as well as NO release from its storage pools. Likewise, NO increases the activity and the expression of H2S-generating enzymes. Inhibition of NO production leads to elimination/attenuation of the cardioprotective effects of H2S. Regarding the increasing interest in the therapeutic applications of NO or H2S-releasing molecules in a variety of diseases, particularly in the cardiovascular disorders, much is to be learned about their function in glucose/insulin metabolism, especially in diabetes. The aim of this review is to provide a better understanding of the individual and the interactive roles of NO and H2S in carbohydrate metabolism.
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Affiliation(s)
- Sevda Gheibi
- Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden.
| | - Alan P Samsonov
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA
| | - Shahsanam Gheibi
- Maternal and Childhood Obesity Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Alexandra B Vazquez
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, NY, USA.
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15
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Abdel-Zaher AO, Abd-Ellatief RB, Aboulhagag NA, Farghaly HSM, Al-Wasei FMM. The interrelationship between gasotransmitters and lead-induced renal toxicity in rats. Toxicol Lett 2019; 310:39-50. [PMID: 30980911 DOI: 10.1016/j.toxlet.2019.04.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 03/06/2019] [Accepted: 04/08/2019] [Indexed: 12/18/2022]
Abstract
This study explored the role of gasotransmitters in lead-induced nephrotoxicity. Long-term exposure of rats to lead resulted in its accumulation in kidney. The accumulated metal impaired kidney function and structure. Lead intoxication resulted in oxidative stress, inflammation and apoptosis in kidney. In addition, it resulted in nitric oxide (NO) overproduction and decrease in hydrogen sulfide (H2S) level and heme oxygenase (HO-1) concentration in kidney. Inhibition of NO overproduction by L-N(G)-nitroarginine methyl ester (L-NAME) and increasing of H2S level by sodium hydrosulfide (NaHS) and CO level by carbon monoxide-releasing molecule-A1 (CORM-A1) inhibited lead-induced impairment of kidney function and structure. These agents inhibited lead-intoxication induced oxidative stress, inflammation, apoptosis, nitrosative stress and reduction of H2S level and HO-1 concentration. Also, concomitant treatment with these agents inhibited lead intoxication-induced increase in protein expressions of inducible NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and caspase-3 as well as decrease in protein expressions of HO-1 and cystathionine- γ-lyase (CSE) in kidney. The NO donor, L-arginine and the H2S and CO biosynthesis inhibitors, trifluoro-DL-alanine and zinc deutroporphyrin, respectively produced opposite effects and aggravated the toxic effects of lead. These results demonstrate, for the first time, that gasotransmitters play an important role in lead-induced nephrotoxicity.
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Affiliation(s)
- Ahmed O Abdel-Zaher
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | - Rasha B Abd-Ellatief
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Noha A Aboulhagag
- Department of Patholology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Hanan S M Farghaly
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Fahmy M M Al-Wasei
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
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16
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Coletti R, de Lima JBM, Vechiato FMV, de Oliveira FL, Debarba LK, Almeida-Pereira G, Elias LLK, Antunes-Rodrigues J. Nitric oxide acutely modulates hypothalamic and neurohypophyseal carbon monoxide and hydrogen sulphide production to control vasopressin, oxytocin and atrial natriuretic peptide release in rats. J Neuroendocrinol 2019; 31:e12686. [PMID: 30633838 DOI: 10.1111/jne.12686] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 01/07/2019] [Accepted: 01/07/2019] [Indexed: 12/11/2022]
Abstract
Nitric oxide (NO) negatively modulates the secretion of vasopressin (AVP), oxytocin (OT) and atrial natriuretic peptide (ANP) induced by the increase in extracellular osmolality, whereas carbon monoxide (CO) and hydrogen sulphide (H2 S) act to potentiate it; however, little information is available for the osmotic challenge model about whether and how such gaseous systems modulate each other. Therefore, using an acute ex vivo model of hypothalamic and neurohypophyseal explants (obtained from male 6/7-week-old Wistar rats) under conditions of extracellular iso- and hypertonicity, we determined the effects of NO (600 μmol L-1 sodium nitroprusside), CO (100 μmol L-1 tricarbonylchloro[glycinato]ruthenium [II]) and H2 S (10 mmol L-1 sodium sulphide) donors and nitric oxide synthase (NOS) (300 μmol L-1 Nω -methyl-l-arginine [LNMMA]), haeme oxygenase (HO) (200 μmol L-1 Zn(II) deuteroporphyrin IX 2,4-bis-ethylene glycol [ZnDPBG]) and cystathionine β-synthase (CBS) (100 μmol L-1 aminooxyacetate [AOA]) inhibitors on the release of hypothalamic ANP and hypothalamic and neurohypophyseal AVP and OT, as well as on the activities of NOS, HO and CBS. LNMMA reversed hyperosmolality-induced NOS activity, and enhanced hormonal release by the hypothalamus and neurohypophysis, in addition to increasing CBS and hypothalamic HO activity. AOA decreased hypothalamic and neurohypophyseal CBS activity and hormonal release, whereas ZnDPBG inhibited HO activity and hypothalamic hormone release; however, in both cases, AOA did not modulate NOS and HO activity and ZnDPBG did not affect NOS and CBS activity. Thus, our data indicate that, although endogenous CO and H2 S positively modulate AVP, OT and ANP release, only NO plays a concomitant role of modulator of hormonal release and CBS activity in the hypothalamus and neurohypophysis and that of HO activity in the hypothalamus during an acute osmotic stimulus, which suggests that NO is a key gaseous controller of the neuroendocrine system.
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Affiliation(s)
- Ricardo Coletti
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | | | | | | | - Lucas Kniess Debarba
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Gislaine Almeida-Pereira
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | | | - José Antunes-Rodrigues
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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Abdulle AE, van Goor H, Mulder DJ. Hydrogen Sulfide: A Therapeutic Option in Systemic Sclerosis. Int J Mol Sci 2018; 19:E4121. [PMID: 30572591 PMCID: PMC6320961 DOI: 10.3390/ijms19124121] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/07/2018] [Accepted: 12/17/2018] [Indexed: 12/11/2022] Open
Abstract
Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H₂S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H₂S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide, which is known to have several effects, including a strong antioxidant and vasodilator effect, could potentially play a prominent role in the initiation and progression of vasculopathy. A better understanding of the actions of gasotransmitters, like H₂S, in the development of SSc-related vasculopathy, could help to create early interventions to attenuate the disease course. This paper will review the role of H₂S in vascular (patho-)physiology and potential disturbances in SSc. Moreover, current data from experimental animal studies will be reviewed. Lastly, we will evaluate potential interventional strategies.
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Affiliation(s)
- Amaal Eman Abdulle
- Department of Internal Medicine, Division Vascular Medicine, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
| | - Harry van Goor
- Department of Pathology and Medical Biology, Section Pathology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
| | - Douwe J Mulder
- Department of Internal Medicine, Division Vascular Medicine, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
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18
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Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6290931. [PMID: 30050658 PMCID: PMC6040266 DOI: 10.1155/2018/6290931] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 03/13/2018] [Indexed: 01/06/2023]
Abstract
Hydrogen sulfide (H2S) has emerged as a relevant signaling molecule in physiology, taking its seat as a bona fide gasotransmitter akin to nitric oxide (NO) and carbon monoxide (CO). After being merely regarded as a toxic poisonous molecule, it is now recognized that mammalian cells are equipped with sophisticated enzymatic systems for H2S production and breakdown. The signaling role of H2S is mainly related to its ability to modify different protein targets, particularly by promoting persulfidation of protein cysteine residues and by interacting with metal centers, mostly hemes. H2S has been shown to regulate a myriad of cellular processes with multiple physiological consequences. As such, dysfunctional H2S metabolism is increasingly implicated in different pathologies, from cardiovascular and neurodegenerative diseases to cancer. As a highly diffusible reactive species, the intra- and extracellular levels of H2S have to be kept under tight control and, accordingly, regulation of H2S metabolism occurs at different levels. Interestingly, even though H2S, NO, and CO have similar modes of action and parallel regulatory targets or precisely because of that, there is increasing evidence of a crosstalk between the three gasotransmitters. Herein are reviewed the biochemistry, metabolism, and signaling function of hydrogen sulfide, as well as its interplay with the other gasotransmitters, NO and CO.
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19
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Kashfi K. The dichotomous role of H 2S in cancer cell biology? Déjà vu all over again. Biochem Pharmacol 2018; 149:205-223. [PMID: 29397935 PMCID: PMC5866221 DOI: 10.1016/j.bcp.2018.01.042] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/17/2018] [Indexed: 02/09/2023]
Abstract
Nitric oxide (NO) a gaseous free radical is one of the ten smallest molecules found in nature, while hydrogen sulfide (H2S) is a gas that bears the pungent smell of rotten eggs. Both are toxic yet they are gasotransmitters of physiological relevance. There appears to be an uncanny resemblance between the general actions of these two gasotransmitters in health and disease. The role of NO and H2S in cancer has been quite perplexing, as both tumor promotion and inflammatory activities as well as anti-tumor and antiinflammatory properties have been described. These paradoxes have been explained for both gasotransmitters in terms of each having a dual or biphasic effect that is dependent on the local flux of each gas. In this review/commentary, I have discussed the major roles of NO and H2S in carcinogenesis, evaluating their dual nature, focusing on the enzymes that contribute to this paradox and evaluate the pros and cons of inhibiting or inducing each of these enzymes.
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Affiliation(s)
- Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA.
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20
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Gheibi S, Jeddi S, Kashfi K, Ghasemi A. Regulation of vascular tone homeostasis by NO and H 2S: Implications in hypertension. Biochem Pharmacol 2018; 149:42-59. [PMID: 29330066 PMCID: PMC5866223 DOI: 10.1016/j.bcp.2018.01.017] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 01/05/2018] [Indexed: 02/09/2023]
Abstract
Nitric oxide (NO) and hydrogen sulfide (H2S) are two gasotransmitters that are produced in the vasculature and contribute to the regulation of vascular tone. NO and H2S are synthesized in both vascular smooth muscle and endothelial cells; NO functions primarily through the sGC/cGMP pathway, and H2S mainly through activation of the ATP-dependent potassium channels; both leading to relaxation of vascular smooth muscle cells. A deficit in the NO/H2S homeostasis is involved in the pathogenesis of various cardiovascular diseases, especially hypertension. It is now becoming increasingly clear that there are important interactions between NO and H2S and that have a profound impact on vascular tone and this may provide insights into the new therapeutic interventions. The aim of this review is to provide a better understanding of individual and interactive roles of NO and H2S in vascular biology. Overall, available data indicate that both NO and H2S contribute to vascular (patho)physiology and in regulating blood pressure. In addition, boosting NO and H2S using various dietary sources or donors could be a hopeful therapeutic strategy in the management of hypertension.
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Affiliation(s)
- Sevda Gheibi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurophysiology Research Center and Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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21
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Oláh G, Módis K, Törö G, Hellmich MR, Szczesny B, Szabo C. Role of endogenous and exogenous nitric oxide, carbon monoxide and hydrogen sulfide in HCT116 colon cancer cell proliferation. Biochem Pharmacol 2018; 149:186-204. [PMID: 29074106 PMCID: PMC5866187 DOI: 10.1016/j.bcp.2017.10.011] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 10/20/2017] [Indexed: 02/06/2023]
Abstract
The role of the three gasotransmitter systems - nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) - in cancer cells has not yet been studied simultaneously in the same experimental system. We measured the expression of NO and CO and H2S generating enzymes in primary colon cancer tissues and HCT116 colon cancer cells, and evaluated the effect of their pharmacological inhibition or pharmacological donation on cell proliferation. Increased expression of iNOS, nNOS, HO-1, CBS and 3-MST was detected in colon cancer. Inhibitors of NOS, HO-1/2, CBS/CSE and 3-MST, at lower concentrations, slightly stimulated HCT116 cell proliferation, but inhibited proliferation at higher concentrations. Donors of NO, CO or H2S inhibited HCT116 proliferation in a concentration-dependent manner. Inhibition of the cGMP/VASP pathway, Akt and p44/42 MAPK (Erk1/2) inhibited HCT116 cell proliferation. Endogenous NO and H2S biosynthesis were found to play a role in the maintenance of the activity of the cGMP/VASP pathway in HCT116 cells. We conclude that each of the three gasotransmitters play similar, bell-shaped roles in the control of HCT116 cell proliferation: endogenously produced NO, CO and H2S, at an optimal concentration, support HCT116 proliferation; inhibition of their production (which decreases gasotransmitter levels below optimal concentrations) as well as exogenous delivery of these gasotransmitters (which increases gasotransmitter levels above optimal concentrations) suppresses colon cancer cell proliferation. The current data give a mechanistic explanation for the paradoxical finding that both inhibitors and donors of NO, CO and H2S exert anticancer actions in cancer cells.
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Affiliation(s)
- Gabor Oláh
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA
| | - Katalin Módis
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA; Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
| | - Gabor Törö
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA
| | - Mark R Hellmich
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
| | - Bartosz Szczesny
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA
| | - Csaba Szabo
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA.
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22
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Jin S, Teng X, Xiao L, Xue H, Guo Q, Duan X, Chen Y, Wu Y. Hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease by the Akt/eNOS/NO pathway. Exp Biol Med (Maywood) 2017; 242:1831-1841. [PMID: 28971696 DOI: 10.1177/1535370217732325] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of hypertension; however, no studies have examined the functional role of hydrogen sulfide in hypertensive heart disease. We hypothesized that the endogenous production of hydrogen sulfide would be reduced and exogenous hydrogen sulfide would ameliorate cardiac dysfunction in Nω-nitro- L-arginine methyl ester ( L-NAME)-induced hypertensive rats. Therefore, this study investigated the cardioprotective effects of hydrogen sulfide on L-NAME-induced hypertensive heart disease and explored potential mechanisms. The rats were randomly divided into five groups: Control, Control + sodium hydrosulfide (NaHS), L-NAME, L-NAME + NaHS, and L-NAME + NaHS + glibenclamide (Gli) groups. Systolic blood pressure was monitored each week. In Langendorff-isolated rat heart, cardiac function represented by ±LV dP/dtmax and left ventricular developing pressure was recorded after five weeks of treatment. Hematoxylin and Eosin and Masson's trichrome staining and myocardium ultrastructure under transmission electron microscopy were used to evaluate cardiac remodeling. The plasma nitric oxide and hydrogen sulfide concentrations, as well as nitric oxide synthases and cystathionine-γ-lyase activity in left ventricle tissue were determined. The protein expression of p-Akt, Akt, p-eNOS, and eNOS in left ventricle tissue was analyzed using Western blot. After five weeks of L-NAME treatment, there was a time-dependent hypertension, cardiac remodeling, and dysfunction accompanied by a decrease in eNOS phosphorylation, nitric oxide synthase activity, and nitric oxide concentration. Meanwhile, cystathionine-γ-lyase activity and hydrogen sulfide concentration were also decreased. NaHS treatment significantly increased plasma hydrogen sulfide concentration and subsequently promoted the Akt/eNOS/NO pathway which inhibited the development of hypertension and attenuated cardiac remodeling and dysfunction. The cardioprotective effects of NaHS were counteracted by Gli which inhibited the Akt/eNOS/NO pathway. This suggests that the effects of hydrogen sulfide were mediated by the activation of the KATP channels. In conclusion, hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease via the activation of the Akt/eNOS/NO pathway, which was mediated by KATP channels. Impact statement 1. We found that H2S ameliorated L-NAME-induced cardiac remodeling and dysfunction, and played a protective role in L-NAME-induced hypertensive heart disease, which the existing studies have not reported. 2. H2S activated the Akt/eNOS/NO pathway, thereby playing a cardioprotective role in L-NAME-induced hypertensive heart disease. 3. The cardioprotective effect of H2S was mediated by ATP-sensitive potassium channels.
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Affiliation(s)
- Sheng Jin
- 1 Department of Physiology, Hebei Medical University, Hebei 050017, China
| | - Xu Teng
- 1 Department of Physiology, Hebei Medical University, Hebei 050017, China
| | - Lin Xiao
- 1 Department of Physiology, Hebei Medical University, Hebei 050017, China
| | - Hongmei Xue
- 1 Department of Physiology, Hebei Medical University, Hebei 050017, China
| | - Qi Guo
- 1 Department of Physiology, Hebei Medical University, Hebei 050017, China
| | - Xiaocui Duan
- 1 Department of Physiology, Hebei Medical University, Hebei 050017, China
| | - Yuhong Chen
- 1 Department of Physiology, Hebei Medical University, Hebei 050017, China
| | - Yuming Wu
- 1 Department of Physiology, Hebei Medical University, Hebei 050017, China.,2 Hebei Collaborative Innovation Center for Cardio-Cerebrovascular Disease, Hebei 050017, China.,3 Key Laboratory of Vascular Medicine of Hebei Province, Hebei 050017, China
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23
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Nalli AD, Bhattacharya S, Wang H, Kendig DM, Grider JR, Murthy KS. Augmentation of cGMP/PKG pathway and colonic motility by hydrogen sulfide. Am J Physiol Gastrointest Liver Physiol 2017; 313:G330-G341. [PMID: 28705807 PMCID: PMC5668569 DOI: 10.1152/ajpgi.00161.2017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 06/26/2017] [Accepted: 06/27/2017] [Indexed: 01/31/2023]
Abstract
Hydrogen sulfide (H2S), like nitric oxide (NO), causes smooth muscle relaxation, but unlike NO, does not stimulate soluble guanylyl cyclase (sGC) activity and generate cyclic guanosine 5'-monophosphate (cGMP). The aim of this study was to investigate the interplay between NO and H2S in colonic smooth muscle. In colonic smooth muscle from rabbit, mouse, and human, l-cysteine, substrate of cystathionine-γ-lyase (CSE), or NaHS, an H2S donor, inhibited phosphodiesterase 5 (PDE5) activity and augmented the increase in cGMP levels, IP3 receptor phosphorylation at Ser1756 (measured as a proxy for PKG activation), and muscle relaxation in response to NO donor S-nitrosoglutathione (GSNO), suggesting augmentation of cGMP/PKG pathway by H2S. The inhibitory effect of l-cysteine, but not NaHS, on PDE5 activity was blocked in cells transfected with CSE siRNA or treated with CSE inhibitor d,l-propargylglycine (dl-PPG), suggesting activation of CSE and generation of H2S in response to l-cysteine. H2S levels were increased in response to l-cysteine, and the effect of l-cysteine was augmented by GSNO in a cGMP-dependent protein kinase-sensitive manner, suggesting augmentation of CSE/H2S by cGMP/PKG pathway. As a result, GSNO-induced relaxation was inhibited by dl-PPG. In flat-sheet preparation of colon, l-cysteine augmented calcitonin gene-related peptide release in response to mucosal stimulation, and in intact segments, l-cysteine increased the velocity of pellet propulsion. These results demonstrate that in colonic smooth muscle, there is a novel interplay between NO and H2S. NO generates H2S via cGMP/PKG pathway, and H2S, in turn, inhibits PDE5 activity and augments NO-induced cGMP levels. In the intact colon, H2S promotes colonic transit.NEW & NOTEWORTHY Hydrogen sulfide (H2S) and nitric oxide (NO) are important regulators of gastrointestinal motility. The studies herein provide the cross talk between NO and H2S signaling to mediate smooth muscle relaxation and colonic transit. H2S inhibits phosphodiesterase 5 activity to augment cGMP levels in response to NO, which, in turn, via cGMP/PKG pathway, generates H2S. These studies suggest that interventions targeted at restoring NO and H2S homeostasis within the smooth muscle may provide novel therapeutic approaches to mitigate motility disorders.
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Affiliation(s)
- Ancy D Nalli
- Department of Physiology and Biophysics, Virginia Commonwealth University Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Sayak Bhattacharya
- Department of Physiology and Biophysics, Virginia Commonwealth University Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Hongxia Wang
- Department of Physiology and Biophysics, Virginia Commonwealth University Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Derek M Kendig
- Department of Physiology and Biophysics, Virginia Commonwealth University Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - John R Grider
- Department of Physiology and Biophysics, Virginia Commonwealth University Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
| | - Karnam S Murthy
- Department of Physiology and Biophysics, Virginia Commonwealth University Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia
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24
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Yang R, Jia Q, Liu XF, Wang YY, Ma SF. Effects of hydrogen sulfide on inducible nitric oxide synthase activity and expression of cardiomyocytes in diabetic rats. Mol Med Rep 2017; 16:5277-5284. [PMID: 28849194 PMCID: PMC5647082 DOI: 10.3892/mmr.2017.7247] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 08/08/2017] [Indexed: 01/08/2023] Open
Abstract
The aim of the present study was to investigate the effects of hydrogen sulfide (H2S) on the activity and expression of inducible nitric oxide synthase (iNOS) in the myocardial tissue of type 1 diabetic rats. Rats were divided randomly into four groups: Normal control (NC), diabetes mellitus (DM), DM+DL-Proparglygylcine (DM+PAG) and DM+sodium hydrosulfide (DM+NaHS) groups. Type 1 diabetes was induced in the respective groups by a single intraperitoneal (i.p.) injection of streptozotocin. Rats in the DM+PAG and DM+NaHS groups were injected with PAG and NaHS (i.p.) once a day, respectively. The level of fasting blood glucose (FBG), the heart-weight to body-weight (HW/BW) ratio and the ventricular hemodynamic parameters were measured. The activities of serum total NOS (tNOS), iNOS, lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase MB isozyme (CK-MB), and the content of nitric oxide (NO) were detected. The contents of myocardial malondialdehyde (MDA) and NO, and the activities of superoxide dismutase (SOD), tNOS and iNOS were determined. The myocardial tissue was examined for histological and ultrastructural alterations. The expression level of iNOS at the transcriptional and translational levels in the myocardial tissue was estimated. The level of FBG was increased in the DM group compared with the NC group, verifying the diabetic condition of the rats. The function of the left ventricle, the myocardial histological alterations and ultrastructures were damaged in the DM group. The DM group additionally demonstrated an increase in the serum NO content and tNOS, iNOS, LDH, CK and CK-MB activities. The myocardial MDA, NO content and tNOS levels were additionally increased in this group. The iNOS activity was increased significantly whereas the myocardial SOD activity was decreased. The increase in the iNOS activity was supported by an enhanced expression level of myocardial iNOS mRNA and protein in the DM group. In the DM+PAG group, in the absence of H2S, the dysfunction of the left ventricle and the oxidative stress injury were increased compared with the DM group. The activity and the expression of tNOS and iNOS were increased significantly. However, the rats in the DM+PAG group demonstrated the opposite effects. In conclusion, H2S exhibits a protective effect on the myocardium in type 1 diabetic rats, which may be associated with the suppression of iNOS activity and expression, a decrease in the NO content and the inhibition of oxidative stress injury.
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Affiliation(s)
- Rui Yang
- Department of Physiology, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Qiang Jia
- Department of Physiology, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Xiao-Fen Liu
- Department of Physiology, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Yuan-Yuan Wang
- Center of Functional Experiment, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Shan-Feng Ma
- Department of Physiology, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
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Caprnda M, Qaradakhi T, Hart JL, Kobyliak N, Opatrilova R, Kruzliak P, Zulli A. H 2S causes contraction and relaxation of major arteries of the rabbit. Biomed Pharmacother 2017; 89:56-60. [PMID: 28214688 DOI: 10.1016/j.biopha.2017.01.057] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/05/2017] [Accepted: 01/09/2017] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE Cardiovascular disease (CVD) caused by atherosclerosis remains a worldwide burden. Hydrogen sulfide is a promising new therapeutic avenue for the treatment of CVD, however reports show exogenous H2S has both vasodilator and vasoconstrictor effects depending on organ examined, and in vitro studies in animal models which are not resistant to developing atherosclerosis are limited. We sought to determine if rabbit arteries constricted or dilated to hydrogen sulfide. MATERIAL AND METHODS The aorta, carotid, renal and iliac arteries were harvested from New Zealand White rabbits (n=4) and subjected to a concentration response curve to the fast H2S releaser NaHS. In addition, a bolus dose of NaHS was used to determine if further dilation was achievable after maximum dilation to acetylcholine similar to nitric oxide donors. Further, NaHS was used to determine if H2S could impair homocysteine induced endothelial dysfunction. RESULTS Blood vessels relaxed poorly to NaHS and contracted at higher doses. A bolus dose of NaHS relaxed then contracted the aorta, however a bolus dose of NaHS after maximal relaxation to acetylcholine caused marked contraction. NaHS did not prevent homocysteine induced vascular dysfunction. CONCLUSION NaHS at low doses caused minor relaxation of rabbit blood vessels, indicating a possible therapeutic benefit for low dose H2S in the cellular milieu.
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Affiliation(s)
- Martin Caprnda
- 2nd Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
| | - Tawar Qaradakhi
- The Centre for Chronic Disease, College of Health & Biomedicine, Victoria University, Melbourne, Werribee Campus, Victoria, Australia
| | - Joanne L Hart
- School of Health and Biomedical Sciences, RMIT University, Bundoora West, Victoria, Australia
| | - Nazarii Kobyliak
- Department of Endocrinology, Bogomolets National Medical University, Kyiv, Ukraine
| | - Radka Opatrilova
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czechia
| | - Peter Kruzliak
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czechia.
| | - Anthony Zulli
- The Centre for Chronic Disease, College of Health & Biomedicine, Victoria University, Melbourne, Werribee Campus, Victoria, Australia
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Aydinoglu F, Ogulener N. Characterization of relaxant mechanism of H2 S in mouse corpus cavernosum. Clin Exp Pharmacol Physiol 2016; 43:503-11. [PMID: 26845078 DOI: 10.1111/1440-1681.12554] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 01/28/2016] [Accepted: 01/29/2016] [Indexed: 01/22/2023]
Abstract
The aim of this study was to investigate the mechanism of H2 S-induced relaxation in mouse corpus cavernosal tissue. l-cysteine (10(-6) × 10(-3) mol/L) and exogenous H2 S (NaHS; 10(-6) to 10(-3) mol/L) induced concentration-dependent relaxation. l-cysteine-induced relaxations was reduced by d,l-propargylglycine, a cystathionine gamma lyase (CSE) inhibitor but not influenced by aminooxyacetic acid, a cystathionine beta synthase (CBS) inhibitor. l-cysteine induced relaxations, but not of those of H2 S diminished in endothelium-denuded tissues. N(ω) -nitro-l-arginine (l-NA; 10(-4) mol/L), a nitric oxide synthase inhibitor, and ODQ (10(-4) mol/L), a guanylyl cyclase inhibitor, increased the H2 S-induced relaxation. Zaprinast (5 × 10(-6) mol/L) and sildenafil (10(-6) mol/L), phosphodiesterase inhibitors, inhibited H2 S-induced relaxation. Adenylyl cyclase inhibitors N-ethylmaleimide (2.5 × 10(-5) mol/L) and SQ22536 (10(-4) mol/L) reduced relaxation to H2 S. Also, H2 S-induced relaxation was reduced by KCl (50 mmol/L), 4-aminopyridine (10(-3) mol/L), a Kv inhibitor, glibenclamide (10(-5) mol/L), a KATP inhibitor or barium chloride (10(-5) mol/L), a KIR inhibitor. However, H2 S-induced relaxation was not influenced by apamin (10(-6) mol/L), a SKC a (2+) inhibitor, charybdotoxin (10(-7) mol/L), an IKC a (2+) and BKC a (2+) inhibitor or combination of apamin and charybdotoxin. Nifedipine (10(-6) mol/L), an L-type calcium channel blocker and atropine (10(-6) mol/L), a muscarinic receptor blocker, inhibited H2 S-induced relaxation. However, H2 S-induced relaxation was not influenced by ouabain (10(-4) mol/L), a Na(+) /K(+) -ATPase inhibitor. This study suggests that H2 S endogenously synthesizes from l-cysteine by CSE endothelium-dependent in mouse corpus cavernosum tissue, and exogenous H2 S may cause endothelium-independent relaxations via activation of K channels (KATP channel, KV channels, KIR channels), L-type voltage-gated Ca(2+) channels, adenylyl cyclase/cAMP pathway and muscarinic receptor, and there is the interaction between H2 S and NO/cGMP.
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Affiliation(s)
- Fatma Aydinoglu
- Department of Pharmacology, Pharmacy Faculty, Çukurova University, Adana, Turkey
| | - Nuran Ogulener
- Department of Pharmacology, Medical Faculty, Çukurova University, Adana, Turkey
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Donnarumma E, Bhushan S, Bradley JM, Otsuka H, Donnelly EL, Lefer DJ, Islam KN. Nitrite Therapy Ameliorates Myocardial Dysfunction via H2S and Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2)-Dependent Signaling in Chronic Heart Failure. J Am Heart Assoc 2016; 5:JAHA.116.003551. [PMID: 27473036 PMCID: PMC5015282 DOI: 10.1161/jaha.116.003551] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Bioavailability of nitric oxide (NO) and hydrogen sulfide (H2S) is reduced in heart failure (HF). Recent studies suggest cross-talk between NO and H2S signaling. We previously reported that sodium nitrite (NaNO2) ameliorates myocardial ischemia-reperfusion injury and HF. Nuclear factor-erythroid-2-related factor 2 (Nrf2) regulates the antioxidant proteins expression and is upregulated by H2S. We examined the NaNO2 effects on endogenous H2S bioavailability and Nrf2 activation in mice subjected to ischemia-induced chronic heart failure (CHF). METHODS AND RESULTS Mice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. NaNO2 (165 μg/kgic) or vehicle was administered at reperfusion and then in drinking water (100 mg/L) for 4 weeks. Left ventricular (LV), ejection fraction (EF), LV end diastolic (LVEDD) and systolic dimensions (LVESD) were determined at baseline and at 4 weeks of reperfusion. Myocardial tissue was analyzed for oxidative stress and respective gene/protein-related assays. We found that NaNO2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia-induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in NaNO2-treated mice as compared to vehicle, suggesting a reduction in oxidative stress. NaNO2 therapy markedly increased expression of Cu,Zn-superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, NaNO2 upregulated the activity of Nrf2, as well as H2S-producing enzymes, and ultimately increased H2S bioavailability in ischemia-induced CHF in mice as compared with vehicle. CONCLUSIONS Our results demonstrate that NaNO2 therapy significantly improves LV function via increasing H2S bioavailability, Nrf2 activation, and antioxidant defenses.
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Affiliation(s)
- Erminia Donnarumma
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA
| | - Shashi Bhushan
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA
| | - Jessica M Bradley
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA
| | - Hiroyuki Otsuka
- Department of Surgery, Kurume University School of Medicine Kurume, Japan
| | - Erinn L Donnelly
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA
| | - David J Lefer
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA
| | - Kazi N Islam
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA
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Mostafa DK, El Azhary NM, Nasra RA. The hydrogen sulfide releasing compounds ATB-346 and diallyl trisulfide attenuate streptozotocin-induced cognitive impairment, neuroinflammation, and oxidative stress in rats: involvement of asymmetric dimethylarginine. Can J Physiol Pharmacol 2016; 94:699-708. [DOI: 10.1139/cjpp-2015-0316] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Hydrogen sulfide (H2S) has attracted interest as a gaseous mediator involved in diverse processes in the nervous system, particularly with respect to learning and memory. However, its therapeutic potential in Alzheimer disease (AD) is not fully explored. Therefore, the effects of H2S-releasing compounds against AD-like behavioural and biochemical abnormalities were investigated. Memory deficit was induced by intracerberoventicular injection of streptozotocin (STZ, 3 mg·kg−1). Animals were randomly assigned into 5 groups (12 rats each): normal control, STZ treated, and 3 drug-treated groups receiving naproxen, H2S-releasing naproxen (ATB-346), and diallyl trisulfide in 20, 32, 40 mg·kg−1·day−1, respectively. Memory function was assessed by passive avoidance and T-maze tasks. After 21 days, hippocampal IL-6, malondialdehyde, reduced glutathione (GSH), asymmetric dimethylarginine (ADMA), and acetylcholinestrase activity were determined. ATB-346 and diallyl trisulfide ameliorated behavioural performance and reduced malondialdehyde, ADMA, and acetylcholinestrase activity while increasing GSH. This study demonstrates the beneficial effects of H2S release in STZ-induced memory impairment by modulation of neuroinflammation, oxidative stress, and cholinergic function. It also delineates the implication of ADMA to the cognitive impairment induced by STZ. These findings draw the attention to H2S-releasing compounds as new candidates for treating neurodegenerative disorders that have prominent oxidative and inflammatory components such as AD.
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Affiliation(s)
- Dalia K. Mostafa
- Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Nesrine M. El Azhary
- Department of Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Rasha A. Nasra
- Department of Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Scuffi D, Lamattina L, García-Mata C. Gasotransmitters and Stomatal Closure: Is There Redundancy, Concerted Action, or Both? FRONTIERS IN PLANT SCIENCE 2016; 7:277. [PMID: 27014301 PMCID: PMC4791407 DOI: 10.3389/fpls.2016.00277] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/21/2016] [Indexed: 05/07/2023]
Affiliation(s)
| | | | - Carlos García-Mata
- Laboratorio de Fisiologia Molecular e Integrativa, Instituto de Investigaciones Biologicas-CONICET, Universidad Nacional de Mar del PlataMar del Plata, Argentina
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Zhao S, Liu FF, Wu YM, Jiang YQ, Guo YX, Wang XL. Upregulation of spinal NMDA receptors mediates hydrogen sulfide-induced hyperalgesia. J Neurol Sci 2016; 363:176-81. [PMID: 27000247 DOI: 10.1016/j.jns.2016.02.058] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 02/04/2016] [Accepted: 02/23/2016] [Indexed: 01/23/2023]
Abstract
Hydrogen sulfide (H2S) is an endogenous neurotransmitter that importantly regulates various physiological and pathological events including pain signal transduction. In this study, we investigated the role of spinal NMDA receptors in the nociception induced by intraplantar injection of NaHS, an H2S donor. Intraplantar injection of NaHS into hindpaw significantly decreased the paw withdrawal threshold (PWT) in contralateral hindpaw. However, intraplantar formalin injection did not produce PWT in contralateral hindpaw. Intrathecal injection of methemoglobin, a H2S scavenger, abolished hyperalgesia induced by NaHS. In addition, NaHS-induced hyperalgesia was partly, but significantly, attenuated by intrathecal injection of hydroxylamine, a cystathionine-β-synthase (CBS) inhibitor. RT-PCR and western blotting analysis revealed that NR2B mRNA and protein levels were increased in the spinal dorsal horn, but not in dorsal root ganglion (DRG) in rats subjected to NaHS intraplantar injection. Collectively, these data suggest that peripheral injection of H2S donor causes hyperalgesia through increase in NR2B expression and production of H2S in the spinal cord.
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Affiliation(s)
- Shuang Zhao
- Department of Anesthesiology, The Third Hospital of HeBei Medical University, China
| | - Fei-Fei Liu
- Department of Anesthesiology, The Third Hospital of HeBei Medical University, China
| | - Yu-Ming Wu
- Department of Physiology, HeBei Medical University, Shijiazhuang, HeBei 050017, China
| | - Yu-Qing Jiang
- Department of Anesthesiology, The Third Hospital of HeBei Medical University, China
| | - Yue-Xian Guo
- Department of Anesthesiology, The Third Hospital of HeBei Medical University, China
| | - Xiu-Li Wang
- Department of Anesthesiology, The Third Hospital of HeBei Medical University, China.
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Moustafa A, Habara Y. Reciprocal interaction among gasotransmitters in isolated pancreatic β-cells. Free Radic Biol Med 2016; 90:47-58. [PMID: 26577175 DOI: 10.1016/j.freeradbiomed.2015.11.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 11/04/2015] [Accepted: 11/09/2015] [Indexed: 11/28/2022]
Abstract
We aimed to elucidate the interplay among the three well-known gas molecules, nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), and their effects on intracellular Ca(2+) concentration ([Ca(2+)]i) and insulin secretion in rat pancreatic β-cells. Immunofluorescence studies demonstrated the expression of constitutive enzymes that are responsible for the production of NO, CO and H2S. CO and H2S increased NO production as indicated by the increase in diaminofluorescein-2 triazole fluorescence. NO and CO induced an elevation in the sulfane sulfur pool and concomitantly H2S production. The NO- and CO-induced H2S production was partially inhibited by hypotaurine, an H2S scavenger. NO and H2S produced CO production as revealed by a myoglobin assay. A calmodulin antagonist in the absence of extracellular Ca(2+) significantly attenuated NO and H2S production. NO and CO induced a [Ca(2+)]i increase mainly via Ca(2+) release from internal stores; however, H2S induced a [Ca(2+)]i increase via the influx of extracellular Ca(2+). NO dose-dependently stimulated basal insulin release but CO dose-dependently inhibited it. H2S showed an insignificant effect on basal insulin secretion from freshly isolated pancreatic islets. Herein, we address for the first time the reciprocal and synergistic relation among gasotransmitters with diverse effects on basal insulin secretion that regulate β-cells functions and homeostasis.
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Affiliation(s)
- Amira Moustafa
- Laboratory of Physiology, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan; Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Yoshiaki Habara
- Laboratory of Physiology, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
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Scuffi D, Lamattina L, García-Mata C. Decoding the Interaction Between Nitric Oxide and Hydrogen Sulfide in Stomatal Movement. GASOTRANSMITTERS IN PLANTS 2016. [DOI: 10.1007/978-3-319-40713-5_13] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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H2S, a novel gasotransmitter, involves in gastric accommodation. Sci Rep 2015; 5:16086. [PMID: 26531221 PMCID: PMC4632036 DOI: 10.1038/srep16086] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/07/2015] [Indexed: 01/19/2023] Open
Abstract
H2S is produced mainly by two enzymes:cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), using L-cysteine (L-Cys) as the substrate. In this study, we investigated the role of H2S in gastric accommodation using CBS+/− mice, immunohistochemistry, immunoblot, methylene blue assay, intragastric pressure (IGP) recording and electrical field stimulation (EFS). Mouse gastric fundus expressed H2S-generating enzymes (CBS and CSE) and generated detectable amounts of H2S. The H2S donor, NaHS or L-Cys, caused a relaxation in either gastric fundus or body. The gastric compliance was significantly increased in the presence of L-Cys (1 mM). On the contrary, AOAA, an inhibitor for CBS, largely inhibited gastric compliance. Consistently, CBS+/− mice shows a lower gastric compliance. However, PAG, a CSE inhibitor, had no effect on gastric compliances. L-Cys enhances the non-adrenergic, non-cholinergic (NANC) relaxation of fundus strips, but AOAA reduces the magnitude of relaxations to EFS. Notably, the expression level of CBS but not CSE protein was elevated after feeding. Consistently, the production of H2S was also increased after feeding in mice gastric fundus. In addition, AOAA largely reduced food intake and body weight in mice. Furthermore, a metabolic aberration of H2S was found in patients with functional dyspepsia (FD). In conclusion, endogenous H2S, a novel gasotransmitter, involves in gastric accommodation.
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Ziogas V, Tanou G, Belghazi M, Filippou P, Fotopoulos V, Grigorios D, Molassiotis A. Roles of sodium hydrosulfide and sodium nitroprusside as priming molecules during drought acclimation in citrus plants. PLANT MOLECULAR BIOLOGY 2015; 89:433-50. [PMID: 26404728 DOI: 10.1007/s11103-015-0379-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 08/31/2015] [Indexed: 05/04/2023]
Abstract
Emerging evidence suggests that the gaseous molecules hydrogen sulfide (H2S) and nitric oxide (NO) enhances plant acclimation to stress; however, the underlying mechanism remains unclear. In this work, we explored if pretreatment of citrus roots with NaHS (a H2S donor) or sodium nitroprusside (SNP, a NO donor) for 2 days (d) could elicit long-lasting priming effects to subsequent exposure to PEG-associated drought stress for 21 d following a 5 d acclimation period. Detailed physiological study documented that both pretreatments primed plants against drought stress. Analysis of the level of nitrite, NOx, S-nitrosoglutahione reductase, Tyr-nitration and S-nitrosylation along with the expression of genes involved in NO-generation suggested that the nitrosative status of leaves and roots was altered by NaHS and SNP. Using a proteomic approach we characterized S-nitrosylated proteins in citrus leaves exposed to chemical treatments, including well known and novel S-nitrosylated targets. Mass spectrometry analysis also enabled the identification of 42 differentially expressed proteins in PEG alone-treated plants. Several PEG-responsive proteins were down-regulated, especially photosynthetic proteins. Finally, the identification of specific proteins that were regulated by NaHS and SNP under PEG conditions provides novel insight into long-term drought priming in plants and in a fruit crop such as citrus in particular.
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Affiliation(s)
- Vasileios Ziogas
- Faculty of Agriculture, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloníki, Greece
| | - Georgia Tanou
- Faculty of Agriculture, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloníki, Greece
| | - Maya Belghazi
- Faculty of Medicine, Proteomics Analysis Center (CAPM), 13916, Marseilles, France
| | - Panagiota Filippou
- Department of Agricultural Sciences, Biotechnology and Food Science, Cyprus University of Technology, 3036, Limassol, Cyprus
| | - Vasileios Fotopoulos
- Faculty of Agriculture, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloníki, Greece
| | - Diamantidis Grigorios
- Faculty of Agriculture, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloníki, Greece
| | - Athanassios Molassiotis
- Faculty of Agriculture, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloníki, Greece.
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Ruginsk SG, Mecawi ADS, da Silva MP, Reis WL, Coletti R, de Lima JBM, Elias LLK, Antunes-Rodrigues J. Gaseous modulators in the control of the hypothalamic neurohypophyseal system. Physiology (Bethesda) 2015; 30:127-38. [PMID: 25729058 DOI: 10.1152/physiol.00040.2014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are gaseous molecules produced by the brain. Within the hypothalamus, gaseous molecules have been highlighted as autocrine and paracrine factors regulating endocrine function. Therefore, in the present review, we briefly discuss the main findings linking NO, CO, and H2S to the control of body fluid homeostasis at the hypothalamic level, with particular emphasis on the regulation of neurohypophyseal system output.
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Affiliation(s)
- Silvia Graciela Ruginsk
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Andre de Souza Mecawi
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Melina Pires da Silva
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Wagner Luis Reis
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and Physiology Department, Georgia Regents University, Augusta, Georgia
| | - Ricardo Coletti
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | | | - Lucila Leico Kagohara Elias
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Jose Antunes-Rodrigues
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil; and
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Duan XC, Liu SY, Guo R, Xiao L, Xue HM, Guo Q, Jin S, Wu YM. Cystathionine-β-Synthase Gene Transfer Into Rostral Ventrolateral Medulla Exacerbates Hypertension via Nitric Oxide in Spontaneously Hypertensive Rats. Am J Hypertens 2015; 28:1106-13. [PMID: 25628417 DOI: 10.1093/ajh/hpu299] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 12/17/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Rostral ventrolateral medulla (RVLM) plays a crucial role in the central regulation of cardiovascular functions. Cystathionine-β-synthase (CBS) is a major hydrogen sulfide (H2S)-generating enzyme that has been identified mainly in the brain. The present study was designed to examine CBS expression and determine its roles and mechanisms of regulating sympathetic outflow and blood pressure (BP) in the RVLM in spontaneously hypertensive rats (SHR). METHODS AND RESULTS CBS expression was decreased in the RVLM in SHR compared to Wistar-Kyoto (WKY) rats. Accumulating evidences suggest that H2S interacts with nitric oxide (NO) to regulate cardiovascular function. Therefore, we hypothesize that the decrease in CBS expression in the RVLM may be involved in the disorder of l-arginine/NO pathway, which subsequently affects BP in SHR. Overexpression of CBS in the RVLM caused significant increases in BP, heart rate, and urinary norepinephrine excretion in SHR but not in WKY. Acute experiments were carried out at day 7 after gene transfer. NO metabolite levels, neuronal NO synthase, and γ-amino butyric acid were decreased in SHR after CBS gene transfer. Furthermore, pressor responses to microinjection of NG-monomethyl-l-arginine into RVLM were blunt in SHR transfected with AdCBS compared to SHR transfected with AdEGFP. CONCLUSIONS Overexpression of CBS in the RVLM elicits enhanced pressor responses in SHR, but not in WKY, and the NO system is involved in these effects. The results suggest that alterations of H2S signaling in the brain may be associated with the development of hypertension.
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Affiliation(s)
- Xiao-Cui Duan
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China; Hebei Key Lab of Laboratory Animal Science, Department of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, China
| | - Shang-Yu Liu
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Rong Guo
- Department of Education Administration, Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lin Xiao
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Hong-Mei Xue
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Qi Guo
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Sheng Jin
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Yu-Ming Wu
- Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China;
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Heine CL, Schmidt R, Geckl K, Schrammel A, Gesslbauer B, Schmidt K, Mayer B, Gorren ACF. Selective Irreversible Inhibition of Neuronal and Inducible Nitric-oxide Synthase in the Combined Presence of Hydrogen Sulfide and Nitric Oxide. J Biol Chem 2015; 290:24932-44. [PMID: 26296888 PMCID: PMC4599001 DOI: 10.1074/jbc.m115.660316] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Indexed: 11/06/2022] Open
Abstract
Citrulline formation by both human neuronal nitric-oxide synthase (nNOS) and mouse macrophage inducible NOS was inhibited by the hydrogen sulfide (H2S) donor Na2S with IC50 values of ∼2.4·10−5 and ∼7.9·10−5m, respectively, whereas human endothelial NOS was hardly affected at all. Inhibition of nNOS was not affected by the concentrations of l-arginine (Arg), NADPH, FAD, FMN, tetrahydrobiopterin (BH4), and calmodulin, indicating that H2S does not interfere with substrate or cofactor binding. The IC50 decreased to ∼1.5·10−5m at pH 6.0 and increased to ∼8.3·10−5m at pH 8.0. Preincubation of concentrated nNOS with H2S under turnover conditions decreased activity after dilution by ∼70%, suggesting irreversible inhibition. However, when calmodulin was omitted during preincubation, activity was not affected, suggesting that irreversible inhibition requires both H2S and NO. Likewise, NADPH oxidation was inhibited with an IC50 of ∼1.9·10−5m in the presence of Arg and BH4 but exhibited much higher IC50 values (∼1.0–6.1·10−4m) when Arg and/or BH4 was omitted. Moreover, the relatively weak inhibition of nNOS by Na2S in the absence of Arg and/or BH4 was markedly potentiated by the NO donor 1-(hydroxy-NNO-azoxy)-l-proline, disodium salt (IC50 ∼ 1.3–2.0·10−5m). These results suggest that nNOS and inducible NOS but not endothelial NOS are irreversibly inhibited by H2S/NO at modest concentrations of H2S in a reaction that may allow feedback inhibition of NO production under conditions of excessive NO/H2S formation.
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Affiliation(s)
| | | | - Kerstin Geckl
- From the Departments of Pharmacology and Toxicology and
| | | | - Bernd Gesslbauer
- Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Karl Franzens University Graz, A-8010 Graz, Austria
| | - Kurt Schmidt
- From the Departments of Pharmacology and Toxicology and
| | - Bernd Mayer
- From the Departments of Pharmacology and Toxicology and
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Kloesch B, Steiner G, Mayer B, Schmidt K. Hydrogen sulfide inhibits endothelial nitric oxide formation and receptor ligand-mediated Ca(2+) release in endothelial and smooth muscle cells. Pharmacol Rep 2015; 68:37-43. [PMID: 26721349 DOI: 10.1016/j.pharep.2015.05.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 05/26/2015] [Accepted: 05/27/2015] [Indexed: 01/15/2023]
Abstract
BACKGROUND In the vascular system, ATP-sensitive K(+)-channels are a target for H2S. Recent evidence suggests that H2S may also modulate Na(+)- and Ca(2+)-permeable channels and intracellular Ca(2+) stores, but the influence of H2S on endothelial Ca(2+) dynamics and Ca(2+)-dependent activation of endothelial nitric oxide synthase (eNOS) is unclear. In this study, we investigated the effects of H2S on Ca(2+) signaling in endothelial and smooth muscle cells with special emphasis given to the role of H2S in modulating endothelial NO formation. METHODS Experiments were performed with endothelial cells from porcine aorta, the human endothelial cell line HMEC-1, and smooth muscle cells from rat aorta and trachea. Mobilization of intracellular Ca(2+) and Ca(2+) entry was monitored with Fura-2. Activity of eNOS was determined as conversion of incorporated l-[(3)H]arginine into l-[(3)H]citrulline. RESULTS Incubation of endothelial cells with the H2S donors sodium hydrogen sulfide (NaHS) and GYY4137 blocked activation of eNOS by the receptor agonist ATP but not by the Ca(2+) ionophore A23187. Data revealed that H2S inhibited ATP-induced release of Ca(2+) from intracellular stores indicating that H2S attenuates eNOS activity by blocking capacitative Ca(2+) entry. A similar inhibitory effect of H2S on ATP-induced Ca(2+) release and Ca(2+) entry was also observed in human microvascular endothelial cells and smooth muscle cells. CONCLUSIONS H2S antagonized Ca(2+) mobilization by receptor agonists and store-operated Ca(2+) entry thereby limiting eNOS activation and NO formation. The effect of H2S on Ca(2+) stores was not restricted to endothelial cells but was also observed in vascular and tracheal smooth muscle cells.
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Affiliation(s)
- Burkhard Kloesch
- Ludwig Boltzmann Institute for Rheumatology and Balneology, Cluster Rheumatology, Balneology and Rehabilitation, Vienna, Austria.
| | - Guenter Steiner
- Ludwig Boltzmann Institute for Rheumatology and Balneology, Cluster Rheumatology, Balneology and Rehabilitation, Vienna, Austria; Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Bernd Mayer
- Department of Pharmacology and Toxicology, Karl-Franzens-University Graz, Graz, Austria
| | - Kurt Schmidt
- Department of Pharmacology and Toxicology, Karl-Franzens-University Graz, Graz, Austria
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Pushpakumar S, Kundu S, Sen U. Endothelial dysfunction: the link between homocysteine and hydrogen sulfide. Curr Med Chem 2015; 21:3662-72. [PMID: 25005183 DOI: 10.2174/0929867321666140706142335] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 04/23/2014] [Accepted: 07/01/2014] [Indexed: 12/30/2022]
Abstract
High level of homocysteine (hyperhomocysteinemia, HHcy) is associated with increased risk for vascular disease. Evidence for this emerges from epidemiological studies which show that HHcy is associated with premature peripheral, coronary artery and cerebrovascular disease independent of other risk factors. Possible mechanisms by which homocysteine causes vascular injury include endothelial injury, DNA dysfunction, proliferation of smooth muscle cells, increased oxidative stress, reduced activity of glutathione peroxidase and promoting inflammation. HHcy has been shown to cause direct damage to endothelial cells both in vitro and in vivo. Clinically, this manifests as impaired flow-mediated vasodilation and is mainly due to a reduction in nitric oxide synthesis and bioavailability. The effect of impaired nitric oxide release can in turn trigger and potentiate atherothrombogenesis and oxidative stress. Endothelial damage is a crucial aspect of atherosclerosis and precedes overt manifestation of disease. In addition, endothelial dysfunction is also associated with hypertension, diabetes, ischemia reperfusion injury and neurodegenerative diseases. Homocysteine is a precursor of hydrogen sulfide (H2S) which is formed by transulfuration process catalyzed by the enzymes, cystathionine β-synthase and cystathionine γ-lyase. H2S is a gasotransmitter that has emerged recently as a novel mediator in cardiovascular homeostasis. As a potent vasodilator, it plays several roles which include regulation of vessel diameter, protection of endothelium from redox stress, ischemia reperfusion injury and chronic inflammation. However, the precise mechanism by which it mediates these beneficial effects is complex and still remains unclear. Current evidence indicates H2S modulates cellular functions by a variety of intracellular signaling processes. In this review, we summarize the mechanisms of HHcy-induced endothelial dysfunction and the metabolism and physiological functions of H2S as a protective agent.
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Affiliation(s)
| | | | - Utpal Sen
- Department of Physiology & Biophysics, University of Louisville School of Medicine, 500 South Preston Street, A-1115; Louisville, KY-40292, USA.
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Peter EA, Varma J, Kevil CG. Hydrogen Sulfide. Atherosclerosis 2015. [DOI: 10.1002/9781118828533.ch31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Kutz JL, Greaney JL, Santhanam L, Alexander LM. Evidence for a functional vasodilatatory role for hydrogen sulphide in the human cutaneous microvasculature. J Physiol 2015; 593:2121-9. [PMID: 25639684 DOI: 10.1113/jp270054] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 01/23/2015] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS Hydrogen sulphide (H2 S) is vasoprotective, attenuates inflammation and modulates blood pressure in animal models; however, its specific mechanistic role in the human vasculature remains unclear. In the present study, we report the novel finding that the enzymes responsible for endogenous H2 S production, cystathionine-γ-lyase and 3-mercaptopyruvate sulphurtransferase, are expressed in the human cutaneous circulation. Functionally, we show that H2 S-induced cutaneous vasodilatation is mediated, in part, by tetraethylammonium-sensitive calcium-dependent potassium channels and not by ATP-sensitive potassium channels. In addition, nitric oxide and cyclo-oxygenase-derived byproducts are required for full expression of exogenous H2 S-mediated cutaneous vasodilatation. Future investigations of the potential role for H2 S with respect to modulating vascular function in humans may have important clinical implications for understanding the mechanisms underlying vascular dysfunction characteristic of multiple cardiovascular pathologies. ABSTRACT The present study aimed to identify the presence of cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3-MST), which endogenously produce hydrogen sulphide (H2 S), and to functionally examine the mechanisms of H2 S-induced vasodilatation in the human cutaneous microcirculation. CSE and 3-MST were quantified in forearm skin samples from 5 healthy adults (24 ± 3 years) using western blot analysis. For functional studies, microdialysis fibres were placed in the forearm skin of 12 healthy adults (25 ± 3 years) for graded infusions (0.01-100 mm) of sodium sulphide (Na2 S) and sodium hydrogen sulphide (NaHS). To define the mechanisms mediating H2 S-induced vasodilatation, microdialysis fibres were perfused with Ringer solution (control), a ATP-sensitive potassium channel (KATP ) inhibitor, an intermediate calcium-dependent potassium channel (KCa ) inhibitor, a non-specific KCa channel inhibitor or triple blockade. To determine the interaction of H2 S-mediated vasodilatation with nitric oxide (NO) and cyclo-oxygenase (COX) signalling pathways, microdialysis fibres were perfused with Ringer solution (control), a non-specific NO synthase inhibitor, a non-selective COX inhibitor or combined inhibition during perfusion of increasing doses of Na2 S. CSE and 3-MST were expressed in all skin samples. Na2 S and NaHS elicited dose-dependent vasodilatation. Non-specific KCa channel inhibition and triple blockade blunted Na2 S-induced vasodilatation (P < 0.05), whereas KATP and intermediate KCa channel inhibition had no effect (P > 0.05). Separate and combined inhibition of NO and COX attenuated H2 S-induced vasodilatation (all P < 0.05). CSE and 3-MST are expressed in the human microvasculature. Exogenous H2 S elicits cutaneous vasodilatation mediated by KCa channels and has a functional interaction with both NO and COX vasodilatatory signalling pathways.
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Affiliation(s)
- Jessica L Kutz
- Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park, PA, USA
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Dyson RM, Palliser HK, Latter JL, Kelly MA, Chwatko G, Glowacki R, Wright IMR. Interactions of the gasotransmitters contribute to microvascular tone (dys)regulation in the preterm neonate. PLoS One 2015; 10:e0121621. [PMID: 25807236 PMCID: PMC4373676 DOI: 10.1371/journal.pone.0121621] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 02/02/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND & AIMS Hydrogen sulphide (H2S), nitric oxide (NO), and carbon monoxide (CO) are involved in transitional microvascular tone dysregulation in the preterm infant; however there is conflicting evidence on the interaction of these gasotransmitters, and their overall contribution to the microcirculation in newborns is not known. The aim of this study was to measure the levels of all 3 gasotransmitters, characterise their interrelationships and elucidate their combined effects on microvascular blood flow. METHODS 90 preterm neonates were studied at 24h postnatal age. Microvascular studies were performed by laser Doppler. Arterial COHb levels (a measure of CO) were determined through co-oximetry. NO was measured as nitrate and nitrite in urine. H2S was measured as thiosulphate by liquid chromatography. Relationships between levels of the gasotransmitters and microvascular blood flow were assessed through partial correlation controlling for the influence of gestational age. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow and derive a theoretical model of their interactions. RESULTS No relationship was observed between NO and CO (p = 0.18, r = 0.18). A positive relationship between NO and H2S (p = 0.008, r = 0.28) and an inverse relationship between CO and H2S (p = 0.01, r = -0.33) exists. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow. The model with the best fit is presented. CONCLUSIONS The relationships between NO and H2S, and CO and H2S may be of importance in the preterm newborn, particularly as NO levels in males are associated with higher H2S levels and higher microvascular blood flow and CO in females appears to convey protection against vascular dysregulation. Here we present a theoretical model of these interactions and their overall effects on microvascular flow in the preterm newborn, upon which future mechanistic studies may be based.
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Affiliation(s)
- Rebecca M. Dyson
- Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, 2308, Australia
- Illawarra Health and Medical Research Institute and Graduate School of Medicine, University of Wollongong, NSW, 2522, Australia
| | - Hannah K. Palliser
- Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia
| | - Joanna L. Latter
- Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, 2308, Australia
| | - Megan A. Kelly
- Illawarra Health and Medical Research Institute and Graduate School of Medicine, University of Wollongong, NSW, 2522, Australia
| | - Grazyna Chwatko
- Department of Environmental Chemistry, Faculty of Chemistry, University of Lodz, 90–236, Lodz, Poland
| | - Rafal Glowacki
- Department of Environmental Chemistry, Faculty of Chemistry, University of Lodz, 90–236, Lodz, Poland
| | - Ian M. R. Wright
- Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, 2308, Australia
- Illawarra Health and Medical Research Institute and Graduate School of Medicine, University of Wollongong, NSW, 2522, Australia
- Kaleidoscope Neonatal Intensive Care Unit, John Hunter Children’s Hospital, New Lambton Heights, NSW, 2305, Australia
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Hancock JT, Whiteman M. Hydrogen sulfide signaling: interactions with nitric oxide and reactive oxygen species. Ann N Y Acad Sci 2015; 1365:5-14. [DOI: 10.1111/nyas.12733] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- John T. Hancock
- Faculty of Health and Applied Sciences; University of the West of England; Bristol England
| | - Matthew Whiteman
- University of Exeter Medical School; University of Exeter; Exeter England
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Chai Q, Lu T, Wang XL, Lee HC. Hydrogen sulfide impairs shear stress-induced vasodilation in mouse coronary arteries. Pflugers Arch 2015; 467:329-40. [PMID: 24793048 DOI: 10.1007/s00424-014-1526-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 04/15/2014] [Accepted: 04/16/2014] [Indexed: 01/01/2023]
Abstract
Hydrogen sulfide has emerged as an important endothelium-dependent vasodilator, but its role in shear stress-mediated dilation of coronary arteries is unclear. We examined the role of H2S on shear stress-mediated dilation of isolated mouse coronary arteries. In these vessels, Na2S produced concentration-dependent dilation, which was significantly inhibited by iberiotoxin and by 4-aminopyridine. In addition, BK and Kv currents in mouse coronary smooth muscle cells were directly activated by Na2S, suggesting that H2S produced vasodilation through BK and Kv channel activation. Using a pressure servo controller system, freshly isolated mouse coronary arteries were subjected to physiological levels of shear stress (1 to 25 dynes/cm(2)) and produced graded dilatory responses, but such effects were diminished in the presence of 100 μM Na2S. Pre-incubation with the cystathionine γ-lyase inhibitor, D,L-propargylglycine (PPG), resulted in a paradoxical augmentation of shear stress-mediated vasodilation. However, in the presence of L-NAME or in coronary arteries from eNOS knockout mice, PPG inhibited shear stress-mediated vasodilation, suggesting an interaction between NO and H2S signaling. Na2S inhibited eNOS activity in cultured mouse aortic endothelial cells and reduced the level of phospho-eNOS(serine 1177). These results suggest that both NO and H2S are important shear stress-mediated vasodilators in mouse coronary arteries but there is a complex interaction between these two signaling pathways that results in paradoxical vasoconstrictive effects of H2S through inhibition of NO generation.
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Affiliation(s)
- Qiang Chai
- Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55905, USA,
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Martinez-Cutillas M, Gil V, Mañé N, Clavé P, Gallego D, Martin MT, Jimenez M. Potential role of the gaseous mediator hydrogen sulphide (H2S) in inhibition of human colonic contractility. Pharmacol Res 2015; 93:52-63. [PMID: 25641403 DOI: 10.1016/j.phrs.2015.01.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/21/2015] [Accepted: 01/21/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND Hydrogen sulphide (H2S) is an endogenous signalling molecule that might play a physiologically relevant role in gastrointestinal motility. Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are two enzymes responsible for H2S production. d,l-Propargylglycine (PAG) is a CSE inhibitor whereas both aminooxyacetic acid (AOAA) and hydroxylamine (HA) are CBS inhibitors. The characterization of H2S responses and its mechanism of action are crucial to define H2S function. METHODS Human colonic strips were used to investigate the role of H2S on contractility (muscle bath) and smooth muscle electrophysiology (microelectrodes). NaHS was used as a H2S donor. RESULTS Combination of PAG and AOAA depolarized the smooth muscle (5-6mV, n=4) and elicited a transient increase in tone (260.5±92.8mg, n=12). No effect was observed on neural mediated inhibitory junction potential or relaxation. In the presence of tetrodotoxin 1μM, NaHS concentration-dependently inhibited spontaneous contractions (EC50=329.2μM, n=18). This effect was partially reduced by the guanylyl cyclase inhibitor ODQ 10μM (EC50=2.6μM, n=12) and by l-NNA 1mM (EC50=1.4mM, n=8). NaHS reversibly blocked neural mediated cholinergic (EC50=2mM) and tachykinergic (EC50=5.7mM) contractions. NaHS concentration-dependently reduced the increase in spontaneous mechanical activity (AUC) induced by carbachol (EC50=1.9mM) and NKA (EC50=1.7mM AUC). CONCLUSIONS H2S might be an endogenous gasomediator regulating human colonic contractility. Its inhibitory effect is observed at high concentrations and could be mediated by a direct effect on smooth muscle with a possible synergistic effect with NO, as well as by an interaction with the cholinergic and tachykinergic neural mediated pathways.
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Affiliation(s)
- M Martinez-Cutillas
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - V Gil
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - N Mañé
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - P Clavé
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain; Fundació de Gastroenterologia Dr Vilardell and Department of Surgery, Hospital de Mataró, Mataró, Barcelona, Spain
| | - D Gallego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - M T Martin
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - M Jimenez
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain.
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Abstract
Nitric oxide (NO) and hydrogen sulfide (H2S) are two major gaseous signaling molecules that regulate diverse physiological functions. Recent publications indicate the regulatory role of H2S on NO metabolism. In this chapter, we discuss the latest findings on H2S-NO interactions through formation of novel chemical derivatives and experimental approaches to study these adducts. This chapter also addresses potential H2S interference on various NO detection techniques, along with precautions for analyzing biological samples from various sources. This information will facilitate critical evaluation and clearer insight into H2S regulation of NO signaling and its influence on various physiological functions.
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Affiliation(s)
- Gopi K Kolluru
- Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA.
| | - Shuai Yuan
- Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Xinggui Shen
- Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Christopher G Kevil
- Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA.
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Hydrogen Sulfide and Reactive Friends: The Interplay with Reactive Oxygen Species and Nitric Oxide Signalling Pathways. PROCEEDINGS OF THE INTERNATIONAL PLANT SULFUR WORKSHOP 2015. [DOI: 10.1007/978-3-319-20137-5_16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Hydrogen sulfide and endothelium-dependent vasorelaxation. Molecules 2014; 19:21183-99. [PMID: 25521118 PMCID: PMC6271169 DOI: 10.3390/molecules191221183] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 12/09/2014] [Accepted: 12/09/2014] [Indexed: 12/20/2022] Open
Abstract
In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H2S), synthesized enzymatically from l-cysteine or l-homocysteine, is the third gasotransmitter in mammals. Endogenous H2S is involved in the regulation of many physiological processes, including vascular tone. Although initially it was suggested that in the vascular wall H2S is synthesized only by smooth muscle cells and relaxes them by activating ATP-sensitive potassium channels, more recent studies indicate that H2S is synthesized in endothelial cells as well. Endothelial H2S production is stimulated by many factors, including acetylcholine, shear stress, adipose tissue hormone leptin, estrogens and plant flavonoids. In some vascular preparations H2S plays a role of endothelium-derived hyperpolarizing factor by activating small and intermediate-conductance calcium-activated potassium channels. Endothelial H2S signaling is up-regulated in some pathologies, such as obesity and cerebral ischemia-reperfusion. In addition, H2S activates endothelial NO synthase and inhibits cGMP degradation by phosphodiesterase 5 thus potentiating the effect of NO-cGMP pathway. Moreover, H2S-derived polysulfides directly activate protein kinase G. Finally, H2S interacts with NO to form nitroxyl (HNO)-a potent vasorelaxant. H2S appears to play an important and multidimensional role in endothelium-dependent vasorelaxation.
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Scuffi D, Álvarez C, Laspina N, Gotor C, Lamattina L, García-Mata C. Hydrogen sulfide generated by L-cysteine desulfhydrase acts upstream of nitric oxide to modulate abscisic acid-dependent stomatal closure. PLANT PHYSIOLOGY 2014; 166:2065-76. [PMID: 25266633 PMCID: PMC4256879 DOI: 10.1104/pp.114.245373] [Citation(s) in RCA: 171] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Accepted: 09/23/2014] [Indexed: 05/20/2023]
Abstract
Abscisic acid (ABA) is a well-studied regulator of stomatal movement. Hydrogen sulfide (H2S), a small signaling gas molecule involved in key physiological processes in mammals, has been recently reported as a new component of the ABA signaling network in stomatal guard cells. In Arabidopsis (Arabidopsis thaliana), H2S is enzymatically produced in the cytosol through the activity of l-cysteine desulfhydrase (DES1). In this work, we used DES1 knockout Arabidopsis mutant plants (des1) to study the participation of DES1 in the cross talk between H2S and nitric oxide (NO) in the ABA-dependent signaling network in guard cells. The results show that ABA did not close the stomata in isolated epidermal strips of des1 mutants, an effect that was restored by the application of exogenous H2S. Quantitative reverse transcription polymerase chain reaction analysis demonstrated that ABA induces DES1 expression in guard cell-enriched RNA extracts from wild-type Arabidopsis plants. Furthermore, stomata from isolated epidermal strips of Arabidopsis ABA receptor mutant pyrabactin-resistant1 (pyr1)/pyrabactin-like1 (pyl1)/pyl2/pyl4 close in response to exogenous H2S, suggesting that this gasotransmitter is acting downstream, although acting independently of the ABA receptor cannot be ruled out with this data. However, the Arabidopsis clade-A PROTEIN PHOSPHATASE2C mutant abscisic acid-insensitive1 (abi1-1) does not close the stomata when epidermal strips were treated with H2S, suggesting that H2S required a functional ABI1. Further studies to unravel the cross talk between H2S and NO indicate that (1) H2S promotes NO production, (2) DES1 is required for ABA-dependent NO production, and (3) NO is downstream of H2S in ABA-induced stomatal closure. Altogether, data indicate that DES1 is a unique component of ABA signaling in guard cells.
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Affiliation(s)
- Denise Scuffi
- Instituto de Investigaciones Biológicas, Universidad Nacional de Mar del Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, 7600 Mar del Plata, Argentina (D.S., N.L., L.L., C.G.-M.); andInstituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas y Universidad de Sevilla, 41092 Seville, Spain (C.Á., C.G.)
| | - Consolación Álvarez
- Instituto de Investigaciones Biológicas, Universidad Nacional de Mar del Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, 7600 Mar del Plata, Argentina (D.S., N.L., L.L., C.G.-M.); andInstituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas y Universidad de Sevilla, 41092 Seville, Spain (C.Á., C.G.)
| | - Natalia Laspina
- Instituto de Investigaciones Biológicas, Universidad Nacional de Mar del Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, 7600 Mar del Plata, Argentina (D.S., N.L., L.L., C.G.-M.); andInstituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas y Universidad de Sevilla, 41092 Seville, Spain (C.Á., C.G.)
| | - Cecilia Gotor
- Instituto de Investigaciones Biológicas, Universidad Nacional de Mar del Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, 7600 Mar del Plata, Argentina (D.S., N.L., L.L., C.G.-M.); andInstituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas y Universidad de Sevilla, 41092 Seville, Spain (C.Á., C.G.)
| | - Lorenzo Lamattina
- Instituto de Investigaciones Biológicas, Universidad Nacional de Mar del Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, 7600 Mar del Plata, Argentina (D.S., N.L., L.L., C.G.-M.); andInstituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas y Universidad de Sevilla, 41092 Seville, Spain (C.Á., C.G.)
| | - Carlos García-Mata
- Instituto de Investigaciones Biológicas, Universidad Nacional de Mar del Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, 7600 Mar del Plata, Argentina (D.S., N.L., L.L., C.G.-M.); andInstituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas y Universidad de Sevilla, 41092 Seville, Spain (C.Á., C.G.)
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Abstract
Hydrogen sulfide (H2S) has emerged as a key regulator of cardiovascular function. This gasotransmitter is produced in the vasculature and is involved in numerous processes that promote vascular homeostasis, including vasodilation and endothelial cell proliferation. Although H2S plays a role under physiological conditions, it has become clear in recent years that hypoxia modulates the production and action of H2S. Furthermore, there is growing evidence that H2S is cytoprotective in the face of hypoxic insults. This review focuses on the synthesis and signaling of H2S in hypoxic conditions in the vasculature, and highlights recent studies providing evidence that H2S is a potential therapy for preventing tissue damage in hypoxic conditions.
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Affiliation(s)
- Jessica M Osmond
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Nancy L Kanagy
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
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