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Sun HJ, Lu QB, Zhu XX, Ni ZR, Su JB, Fu X, Chen G, Zheng GL, Nie XW, Bian JS. Pharmacology of Hydrogen Sulfide and Its Donors in Cardiometabolic Diseases. Pharmacol Rev 2024; 76:846-895. [PMID: 38866561 DOI: 10.1124/pharmrev.123.000928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 04/13/2024] [Accepted: 06/10/2024] [Indexed: 06/14/2024] Open
Abstract
Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies, including multiomics, intestinal microflora analysis, organoid, and single-cell sequencing techniques, are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assess the current literature to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. SIGNIFICANCE STATEMENT: This comprehensive review covers recent developments in H2S biology and pharmacology in cardiometabolic diseases CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.
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Affiliation(s)
- Hai-Jian Sun
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Qing-Bo Lu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Xue-Xue Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Zhang-Rong Ni
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Jia-Bao Su
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Xiao Fu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Guo Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Guan-Li Zheng
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Xiao-Wei Nie
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Jin-Song Bian
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
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Smimmo M, Casale V, Casillo GM, Mitidieri E, d'Emmanuele di Villa Bianca R, Bello I, Schettino A, Montanaro R, Brancaleone V, Indolfi C, Cirino G, Di Lorenzo A, Bucci M, Panza E, Vellecco V. Hydrogen sulfide dysfunction in metabolic syndrome-associated vascular complications involves cGMP regulation through soluble guanylyl cyclase persulfidation. Biomed Pharmacother 2024; 174:116466. [PMID: 38552439 DOI: 10.1016/j.biopha.2024.116466] [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: 12/22/2023] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 05/01/2024] Open
Abstract
Here, by using in vitro and ex vivo approaches, we elucidate the impairment of the hydrogen sulfide (H2S) pathway in vascular complications associated with metabolic syndrome (MetS). In the in vitro model simulating hyperlipidemic/hyperglycemic conditions, we observe significant hallmarks of endothelial dysfunction, including eNOS/NO signaling impairment, ROS overproduction, and a reduction in CSE-derived H2S. Transitioning to an ex vivo model using db/db mice, a genetic MetS model, we identify a downregulation of CBS and CSE expression in aorta, coupled with a diminished L-cysteine-induced vasorelaxation. Molecular mechanisms of eNOS/NO signaling impairment, dissected using pharmacological and molecular approaches, indicate an altered eNOS/Cav-1 ratio, along with reduced Ach- and Iso-induced vasorelaxation and increased L-NIO-induced contraction. In vivo treatment with the H2S donor Erucin ameliorates vascular dysfunction observed in db/db mice without impacting eNOS, further highlighting a specific action on smooth muscle component rather than the endothelium. Analyzing the NO signaling pathway in db/db mice aortas, reduced cGMP levels were detected, implicating a defective sGC/cGMP signaling. In vivo Erucin administration restores cGMP content. This beneficial effect involves an increased sGC activity, due to enzyme persulfidation observed in sGC overexpressed cells, coupled with PDE5 inhibition. In conclusion, our study demonstrates a pivotal role of reduced cGMP levels in impaired vasorelaxation in a murine model of MetS involving an impairment of both H2S and NO signaling. Exogenous H2S supplementation through Erucin represents a promising alternative in MetS therapy, targeting smooth muscle cells and supporting the importance of lifestyle and nutrition in managing MetS.
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Affiliation(s)
- M Smimmo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - V Casale
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - G M Casillo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - E Mitidieri
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | | | - I Bello
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - A Schettino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - R Montanaro
- Department of Science, University of Basilicata, Potenza, Italy
| | - V Brancaleone
- Department of Science, University of Basilicata, Potenza, Italy
| | - C Indolfi
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - G Cirino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - A Di Lorenzo
- Department of Pathology and Laboratory Medicine Center for Vascular Biology, Weill Cornell Medical College, Cornell University, New York, USA
| | - M Bucci
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
| | - E Panza
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - V Vellecco
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
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Alsaeedi A, Welham S, Rose P, Zhu YZ. The Impact of Drugs on Hydrogen Sulfide Homeostasis in Mammals. Antioxidants (Basel) 2023; 12:antiox12040908. [PMID: 37107283 PMCID: PMC10135325 DOI: 10.3390/antiox12040908] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 04/04/2023] [Accepted: 04/09/2023] [Indexed: 04/29/2023] Open
Abstract
Mammalian cells and tissues have the capacity to generate hydrogen sulfide gas (H2S) via catabolic routes involving cysteine metabolism. H2S acts on cell signaling cascades that are necessary in many biochemical and physiological roles important in the heart, brain, liver, kidney, urogenital tract, and cardiovascular and immune systems of mammals. Diminished levels of this molecule are observed in several pathophysiological conditions including heart disease, diabetes, obesity, and immune function. Interestingly, in the last two decades, it has become apparent that some commonly prescribed pharmacological drugs can impact the expression and activities of enzymes responsible for hydrogen sulfide production in cells and tissues. Therefore, the current review provides an overview of the studies that catalogue key drugs and their impact on hydrogen sulfide production in mammals.
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Affiliation(s)
- Asrar Alsaeedi
- School of Biosciences, University of Nottingham, Loughborough, Leicestershire LE12 5RD, UK
| | - Simon Welham
- School of Biosciences, University of Nottingham, Loughborough, Leicestershire LE12 5RD, UK
| | - Peter Rose
- School of Biosciences, University of Nottingham, Loughborough, Leicestershire LE12 5RD, UK
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Yi-Zhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau, China
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Yang XD, Ju B, Xu J, Xiu NN, Sun XY, Zhao XC. Glucocorticoid-induced thrombotic microangiopathy in paroxysmal nocturnal hemoglobinuria: A case report and review of literature. World J Clin Cases 2023; 11:1799-1807. [PMID: 36970013 PMCID: PMC10037281 DOI: 10.12998/wjcc.v11.i8.1799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/02/2022] [Accepted: 02/08/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Thrombotic microangiopathy (TMA) is a group of disorders that converge on excessive platelet aggregation in the microvasculature, leading to consumptive thrombocytopenia, microangiopathic hemolysis and ischemic end-organ dysfunction. In predisposed patients, TMA can be triggered by many environmental factors. Glucocorticoids (GCs) can compromise the vascular endothelium. However, GC-associated TMA has rarely been reported, which may be due to the lack of awareness of clinicians. Given the high frequency of thrombocytopenia during GC treatment, particular attention should be given to this potentially fatal complication.
CASE SUMMARY An elderly Chinese man had a 12-year history of aplastic anemia (AA) and a 3-year history of paroxysmal nocturnal hemoglobinuria (PNH). Three months earlier, methylprednisolone treatment was initiated at 8 mg/d and increased to 20 mg/d to alleviate complement-mediated hemolysis. Following GC treatment, his platelet counts and hemoglobin levels rapidly decreased. After admission to our hospital, the dose of methylprednisolone was increased to 60 mg/d in an attempt to enhance the suppressive effect. However, increasing the GC dose did not alleviate hemolysis, and his cytopenia worsened. Morphological evaluation of the marrow smears revealed increased cellularity with an increased percentage of erythroid progenitors without evident dysplasia. Cluster of differentiation (CD)55 and CD59 expression was significantly decreased on erythrocytes and granulocytes. In the following days, platelet transfusion was required due to severe thrombocytopenia. Observation of platelet transfusion refractoriness indicated that the exacerbated cytopenia may have been caused by the development of TMA due to GC treatment because the transfused platelet concentrates had no defects in glycosylphosphatidylinositol-anchored proteins. We examined blood smears and found a small number of schistocytes, dacryocytes, acanthocytes and target cells. Discontinuation of GC treatment resulted in rapidly increased platelet counts and steady increases in hemoglobin levels. The patient’s platelet counts and hemoglobin levels returned to the levels prior to GC treatment 4 weeks after GC discontinuation.
CONCLUSION GCs can drive TMA episodes. When thrombocytopenia occurs during GC treatment, TMA should be considered, and GCs should be discontinued.
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Affiliation(s)
- Xiao-Dong Yang
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Bo Ju
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Jia Xu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Nuan-Nuan Xiu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xiao-Yun Sun
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xi-Chen Zhao
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
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Piragine E, Citi V, Lawson K, Calderone V, Martelli A. Regulation of blood pressure by natural sulfur compounds: Focus on their mechanisms of action. Biochem Pharmacol 2022; 206:115302. [PMID: 36265595 DOI: 10.1016/j.bcp.2022.115302] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/10/2022] [Accepted: 10/11/2022] [Indexed: 12/14/2022]
Abstract
Natural sulfur compounds are emerging as therapeutic options for the management of hypertension and prehypertension. They are mainly represented by polysulfides from Alliaceae (i.e., garlic) and isothiocyanates from Brassicaceae (or crucifers). The beneficial cardiovascular effects of these compounds, especially garlic polysulfides, are well known and widely reported both in preclinical and clinical studies. However, only a few authors have linked the ability of natural sulfur compounds to induce vasorelaxation and subsequent antihypertensive effects with their ability to release hydrogen sulfide (H2S) in biological tissue. H2S is an endogenous gasotransmitter involved in vascular tone regulation. Some cardiovascular diseases, such as hypertension, are associated with lower plasma H2S levels. Consequently, exogenous sources of H2S (H2S donors) have been designed and synthesized or identified among secondary plant metabolites as potential therapeutic options. In addition to antioxidant effects due to its chemical properties as a reducing agent, H2S induces vasorelaxation by interacting with a range of molecular targets. The mechanisms of action accounting for H2S-induced vasodilation include opening of vascular potassium channels (such as ATP-sensitive (KATP) and voltage-operated (Kv7) channels), inhibition of 5-phosphodiesterase (5-PDE), and activation of vascular endothelial growth factor receptor-2 (VEGFR-2). These effects may be attributed to H2S-induced S-persulfidation (or S-sulfhydration), which is a posttranslational modification of cysteine residues of many types of proteins resulting in structural and functional alterations (activation/inhibition). Thus, H2S donors, such as natural sulfur compounds, are promising antihypertensive agents with novel mechanisms of action.
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Affiliation(s)
- Eugenia Piragine
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
| | - Valentina Citi
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
| | - Kim Lawson
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy; Interdepartmental Research Center "Nutrafood: Nutraceutica e Alimentazione per la Salute", University of Pisa, 56126 Pisa, Italy; Interdepartmental Research Center "Biology and Pathology of Ageing", University of Pisa, 56126 Pisa, Italy
| | - Alma Martelli
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy; Interdepartmental Research Center "Nutrafood: Nutraceutica e Alimentazione per la Salute", University of Pisa, 56126 Pisa, Italy; Interdepartmental Research Center "Biology and Pathology of Ageing", University of Pisa, 56126 Pisa, Italy.
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Adel M, Elsayed HRH, El-Nablaway M, Hamed S, Eladl A, Fouad S, El Nashar EM, Al-Otaibi ML, Rabei MR. Targeting Hydrogen Sulfide Modulates Dexamethasone-Induced Muscle Atrophy and Microvascular Rarefaction, through Inhibition of NOX4 and Induction of MGF, M2 Macrophages and Endothelial Progenitors. Cells 2022; 11:cells11162500. [PMID: 36010575 PMCID: PMC9406793 DOI: 10.3390/cells11162500] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/06/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
Long-term use of Glucocorticoids produces skeletal muscle atrophy and microvascular rarefaction. Hydrogen sulfide (H2S) has a potential role in skeletal muscle regeneration. However, the mechanisms still need to be elucidated. This is the first study to explore the effect of Sodium hydrosulfide (NaHS) H2S donor, against Dexamethasone (Dex)-induced soleus muscle atrophy and microvascular rarefaction and on muscle endothelial progenitors and M2 macrophages. Rats received either; saline, Dex (0.6 mg/Kg/day), Dex + NaHS (5 mg/Kg/day), or Dex + Aminooxyacetic acid (AOAA), a blocker of H2S (10 mg/Kg/day) for two weeks. The soleus muscle was examined for contractile properties. mRNA expression for Myostatin, Mechano-growth factor (MGF) and NADPH oxidase (NOX4), HE staining, and immunohistochemical staining for caspase-3, CD34 (Endothelial progenitor marker), vascular endothelial growth factor (VEGF), CD31 (endothelial marker), and CD163 (M2 macrophage marker) was performed. NaHS could improve the contractile properties and decrease oxidative stress, muscle atrophy, and the expression of NOX4, caspase-3, Myostatin, VEGF, and CD31 and could increase the capillary density and expression of MGF with a significant increase in expression of CD34 and CD163 as compared to Dex group. However, AOAA worsened the studied parameters. Therefore, H2S can be a promising target to attenuate muscle atrophy and microvascular rarefaction.
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Affiliation(s)
- Mohamed Adel
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Hassan Reda Hassan Elsayed
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
- Department of Anatomy, Faculty of Physical therapy, Horus University, New Damietta 34517, Egypt
- Correspondence: ; Tel.: +20-122-9310-701
| | - Mohammad El-Nablaway
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
- Department of Medical Biochemistry, College of Medicine, Almaarefa University, Riyad 71666, Saudi Arabia
| | - Shereen Hamed
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Amira Eladl
- Department of Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Samah Fouad
- Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Eman Mohamad El Nashar
- Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Benha 13511, Egypt
| | - Mohammed Lafi Al-Otaibi
- Department of Orthopedics, College Medicine, King Khalid University, Abha 61421, Saudi Arabia
| | - Mohammed R. Rabei
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
- Department of Physiology, Faculty of Medicine, King Salman International University, El Tor 46511, Egypt
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β3 Relaxant Effect in Human Bladder Involves Cystathionine γ-Lyase-Derived Urothelial Hydrogen Sulfide. Antioxidants (Basel) 2022; 11:antiox11081480. [PMID: 36009199 PMCID: PMC9405273 DOI: 10.3390/antiox11081480] [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: 07/01/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
It is now well established that the urothelium does not act as a passive barrier but contributes to bladder homeostasis by releasing several signaling molecules in response to physiological and chemical stimuli. Here, we investigated the potential contribution of the hydrogen sulfide (H2S) pathway in regulating human urothelium function in β3 adrenoceptor-mediated relaxation. The relaxant effect of BRL 37344 (0.1–300 µM), a selective β3 adrenoceptor agonist, was evaluated in isolated human bladder strips in the presence or absence of the urothelium. The relaxant effect of BRL 37344 was significantly reduced by urothelium removal. The inhibition of cystathionine-γ-lyase (CSE), but not cystathionine-β-synthase (CBS), significantly reduced the BRL 37344 relaxing effect to the same extent as that given by urothelium removal, suggesting a role for CSE-derived H2S. β3 adrenoceptor stimulation in the human urothelium or in T24 urothelial cells markedly increased H2S and cAMP levels that were reverted by a blockade of CSE and β3 adrenoceptor antagonism. These findings demonstrate a key role for urothelium CSE-derived H2S in the β3 effect on the human bladder through the modulation of cAMP levels. Therefore, the study establishes the relevance of urothelial β3 adrenoceptors in the regulation of bladder tone, supporting the use of β3 agonists in patients affected by an overactive bladder.
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Micheli L, Mitidieri E, Turnaturi C, Vanacore D, Ciampi C, Lucarini E, Cirino G, Ghelardini C, Sorrentino R, Di Cesare Mannelli L, d’Emmanuele di Villa Bianca R. Beneficial Effect of H 2S-Releasing Molecules in an In Vitro Model of Sarcopenia: Relevance of Glucoraphanin. Int J Mol Sci 2022; 23:5955. [PMID: 35682634 PMCID: PMC9180606 DOI: 10.3390/ijms23115955] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 02/01/2023] Open
Abstract
Sarcopenia is a gradual and generalized skeletal muscle (SKM) syndrome, characterized by the impairment of muscle components and functionality. Hydrogen sulfide (H2S), endogenously formed within the body from the activity of cystathionine-γ-lyase (CSE), cystathionine- β-synthase (CBS), and mercaptopyruvate sulfurtransferase, is involved in SKM function. Here, in an in vitro model of sarcopenia based on damage induced by dexamethasone (DEX, 1 μM, 48 h treatment) in C2C12-derived myotubes, we investigated the protective potential of exogenous and endogenous sources of H2S, i.e., glucoraphanin (30 μM), L-cysteine (150 μM), and 3-mercaptopyruvate (150 μM). DEX impaired the H2S signalling in terms of a reduction in CBS and CSE expression and H2S biosynthesis. Glucoraphanin and 3-mercaptopyruvate but not L-cysteine prevented the apoptotic process induced by DEX. In parallel, the H2S-releasing molecules reduced the oxidative unbalance evoked by DEX, reducing catalase activity, O2- levels, and protein carbonylation. Glucoraphanin, 3-mercaptopyruvate, and L-cysteine avoided the changes in myotubes morphology and morphometrics after DEX treatment. In conclusion, in an in vitro model of sarcopenia, an impairment in CBS/CSE/H2S signalling occurs, whereas glucoraphanin, a natural H2S-releasing molecule, appears more effective for preventing the SKM damage. Therefore, glucoraphanin supplementation could be an innovative therapeutic approach in the management of sarcopenia.
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Affiliation(s)
- Laura Micheli
- Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba—Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy; (L.M.); (C.C.); (E.L.); (C.G.)
| | - Emma Mitidieri
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (E.M.); (C.T.); (D.V.); (G.C.); (R.d.d.V.B.)
| | - Carlotta Turnaturi
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (E.M.); (C.T.); (D.V.); (G.C.); (R.d.d.V.B.)
| | - Domenico Vanacore
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (E.M.); (C.T.); (D.V.); (G.C.); (R.d.d.V.B.)
| | - Clara Ciampi
- Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba—Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy; (L.M.); (C.C.); (E.L.); (C.G.)
| | - Elena Lucarini
- Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba—Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy; (L.M.); (C.C.); (E.L.); (C.G.)
| | - Giuseppe Cirino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (E.M.); (C.T.); (D.V.); (G.C.); (R.d.d.V.B.)
| | - Carla Ghelardini
- Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba—Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy; (L.M.); (C.C.); (E.L.); (C.G.)
| | - Raffaella Sorrentino
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy;
| | - Lorenzo Di Cesare Mannelli
- Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba—Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy; (L.M.); (C.C.); (E.L.); (C.G.)
| | - Roberta d’Emmanuele di Villa Bianca
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (E.M.); (C.T.); (D.V.); (G.C.); (R.d.d.V.B.)
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9
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Cirino G, Szabo C, Papapetropoulos A. Physiological roles of hydrogen sulfide in mammalian cells, tissues and organs. Physiol Rev 2022; 103:31-276. [DOI: 10.1152/physrev.00028.2021] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
H2S belongs to the class of molecules known as gasotransmitters, which also includes nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized as endogenous sources of H2S in various cells and tissues: cystathionine g-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). The current article reviews the regulation of these enzymes as well as the pathways of their enzymatic and non-enzymatic degradation and elimination. The multiple interactions of H2S with other labile endogenous molecules (e.g. NO) and reactive oxygen species are also outlined. The various biological targets and signaling pathways are discussed, with special reference to H2S and oxidative posttranscriptional modification of proteins, the effect of H2S on channels and intracellular second messenger pathways, the regulation of gene transcription and translation and the regulation of cellular bioenergetics and metabolism. The pharmacological and molecular tools currently available to study H2S physiology are also reviewed, including their utility and limitations. In subsequent sections, the role of H2S in the regulation of various physiological and cellular functions is reviewed. The physiological role of H2S in various cell types and organ systems are overviewed. Finally, the role of H2S in the regulation of various organ functions is discussed as well as the characteristic bell-shaped biphasic effects of H2S. In addition, key pathophysiological aspects, debated areas, and future research and translational areas are identified A wide array of significant roles of H2S in the physiological regulation of all organ functions emerges from this review.
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Affiliation(s)
- Giuseppe Cirino
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, Switzerland
| | - Andreas Papapetropoulos
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece & Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece
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10
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Donertas Ayaz B, Oliveira AC, Malphurs WL, Redler T, de Araujo AM, Sharma RK, Sirmagul B, Zubcevic J. Central Administration of Hydrogen Sulfide Donor NaHS Reduces Iba1-Positive Cells in the PVN and Attenuates Rodent Angiotensin II Hypertension. Front Neurosci 2021; 15:690919. [PMID: 34602965 PMCID: PMC8479468 DOI: 10.3389/fnins.2021.690919] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 08/10/2021] [Indexed: 12/21/2022] Open
Abstract
Hydrogen sulfide (H2S) is a gaseous signaling molecule with neuromodulatory, anti-inflammatory, and anti-hypertensive effects. Here, we investigate whether chronic intracerebroventricular (ICV) infusion of sodium hydrosulfide (NaHS), an H2S donor, can alleviate angiotensin II (Ang II)-induced hypertension (HTN), improve autonomic function, and impact microglia in the paraventricular nucleus (PVN) of the hypothalamus, a brain region associated with autonomic control of blood pressure (BP) and neuroinflammation in HTN. Chronic delivery of Ang II (200 ng/kg/min, subcutaneous) for 4 weeks produced a typical increase in BP and sympathetic drive and elevated the number of ionized calcium binding adaptor molecule 1-positive (Iba1+) cells in the PVN of male, Sprague-Dawley rats. ICV co-infusion of NaHS (at 30 and/or 60 nmol/h) significantly attenuated these effects of Ang II. Ang II also increased the abundance of cecal Deltaproteobacteria and Desulfovibrionales, among others, which was prevented by ICV NaHS co-infusion at 30 and 60 nmol/h. We observed no differences in circulating H2S between the groups. Our results suggest that central H2S may alleviate rodent HTN independently from circulating H2S via effects on autonomic nervous system and PVN microglia.
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Affiliation(s)
- Basak Donertas Ayaz
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
- Department of Pharmacology, College of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Aline C. Oliveira
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Wendi L. Malphurs
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
| | - Ty Redler
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
| | - Alan Moreira de Araujo
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Ravindra K. Sharma
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Basar Sirmagul
- Department of Pharmacology, College of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Jasenka Zubcevic
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
- Department of Physiology and Pharmacology, Center for Hypertension and Precision Medicine, College of Medicine, University of Toledo, Toledo, OH, United States
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11
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Mitidieri E, Visaggio D, Frangipani E, Turnaturi C, Vanacore D, Provenzano R, Costabile G, Sorrentino R, Ungaro F, Visca P, d'Emmanuele di Villa Bianca R. Intra-tracheal administration increases gallium availability in lung: implications for antibacterial chemotherapy. Pharmacol Res 2021; 170:105698. [PMID: 34058327 DOI: 10.1016/j.phrs.2021.105698] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/11/2021] [Accepted: 05/26/2021] [Indexed: 12/01/2022]
Abstract
The emergence of pan-resistant strains in nosocomial settings underscores the urgent need of novel therapies targeting vital bacterial functions. Bacterial iron metabolism is a fascinating target for new antimicrobials. Iron mimetic metal Ga(III) has been repurposed as an antimicrobial drug, in pre-clinical studies and recent clinical studies have raised the possibility of using Ga(III) for the treatment of P. aeruginosa pulmonary infection. Ga(III) has been approved by FDA for the treatment of cancer, autoimmune and bone resorption disorders. However, some critical issues affect the therapeutic schedule of Ga(III), principally the intra-venous (i.v.) administration, and the nephrotoxicity caused by prolonged administration. Ga(III) aerosolization could represent a viable alternative for treatment of lung infections, since delivery of antimicrobial agents to the airways maximizes drug concentration at the site of infection, improves the therapeutic efficacy, and alleviates systemic toxic effects. We demonstrate the advantage of inhaled vs i.v. administered Ga(III), in terms of bio-distribution and lung acute toxicity, by using a rat model. In vivo results support the use of Ga(III) for inhalation since intra-tracheal Ga(III) delivery improved its persistence in the lung, while the i.v. administration caused rapid clearance and did not allow to attain a significant Ga(III) concentration in this organ. Moreover, local and systemic acute toxicity following intra-tracheal administration was not observed, since no significant signs of inflammation were found. At this stage of evidence, the direct administration of Ga(III) to the lung appears feasible and safe, boosting the development of Ga(III)-based drugs for inhalation therapy.
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Affiliation(s)
- Emma Mitidieri
- Department of Pharmacy, School of Medicine and Surgery, University of Napoli Federico II, Napoli, Italy
| | | | - Emanuela Frangipani
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Carlotta Turnaturi
- Department of Pharmacy, School of Medicine and Surgery, University of Napoli Federico II, Napoli, Italy
| | - Domenico Vanacore
- Department of Pharmacy, School of Medicine and Surgery, University of Napoli Federico II, Napoli, Italy
| | - Romina Provenzano
- Department of Pharmacy, School of Medicine and Surgery, University of Napoli Federico II, Napoli, Italy
| | - Gabriella Costabile
- Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy
| | - Raffaella Sorrentino
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, Italy.
| | - Francesca Ungaro
- Department of Pharmacy, School of Medicine and Surgery, University of Napoli Federico II, Napoli, Italy
| | - Paolo Visca
- Department of Science, Roma Tre University, Rome, Italy
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12
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Chen F, Hao L, Zhu S, Yang X, Shi W, Zheng K, Wang T, Chen H. Potential Adverse Effects of Dexamethasone Therapy on COVID-19 Patients: Review and Recommendations. Infect Dis Ther 2021; 10:1907-1931. [PMID: 34296386 PMCID: PMC8298044 DOI: 10.1007/s40121-021-00500-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
In the context of the coronavirus disease 2019 (COVID-19) pandemic, the global healthcare community has raced to find effective therapeutic agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, dexamethasone is the first and an important therapeutic to significantly reduce the risk of death in COVID-19 patients with severe disease. Due to powerful anti-inflammatory and immunosuppressive effects, dexamethasone could attenuate SARS-CoV-2-induced uncontrolled cytokine storm, severe acute respiratory distress syndrome and lung injury. Nevertheless, dexamethasone treatment is a double-edged sword, as numerous studies have revealed that it has significant adverse impacts later in life. In this article, we reviewed the literature regarding the adverse effects of dexamethasone administration on different organ systems as well as related disease pathogenesis in an attempt to clarify the potential harms that may arise in COVID-19 patients receiving dexamethasone treatment. Overall, taking the threat of COVID19 pandemic into account, we think it is necessary to apply dexamethasone as a pharmaceutical therapy in critical patients. However, its adverse side effects cannot be ignored. Our review will help medical professionals in the prognosis and follow-up of patients treated with dexamethasone. In addition, given that a considerable amount of uncertainty, confusion and even controversy still exist, further studies and more clinical trials are urgently needed to improve our understanding of the parameters and the effects of dexamethasone on patients with SARS-CoV-2 infection.
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Affiliation(s)
- Fei Chen
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China.
| | - Lanting Hao
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Shiheng Zhu
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Xinyuan Yang
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Wenhao Shi
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Kai Zheng
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Tenger Wang
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
| | - Huiran Chen
- Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067, China
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13
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Comas F, Moreno-Navarrete JM. The Impact of H 2S on Obesity-Associated Metabolic Disturbances. Antioxidants (Basel) 2021; 10:antiox10050633. [PMID: 33919190 PMCID: PMC8143163 DOI: 10.3390/antiox10050633] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/19/2021] [Indexed: 12/20/2022] Open
Abstract
Over the last several decades, hydrogen sulfide (H2S) has gained attention as a new signaling molecule, with extensive physiological and pathophysiological roles in human disorders affecting vascular biology, immune functions, cellular survival, metabolism, longevity, development, and stress resistance. Apart from its known functions in oxidative stress and inflammation, new evidence has emerged revealing that H2S carries out physiological functions by targeting proteins, enzymes, and transcription factors through a post-translational modification known as persulfidation. This review article provides a critical overview of the current state of the literature addressing the role of H2S in obesity-associated metabolic disturbances, with particular emphasis on its mechanisms of action in obesity, diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases.
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Affiliation(s)
- Ferran Comas
- Department of Diabetes, Endocrinology and Nutrition, Institut d’Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain;
| | - José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d’Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain;
- Department of Medical Sciences, Universitat de Girona, 17003 Girona, Spain
- Correspondence: ; Tel.: +(34)-872-98-70-87
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14
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Ciccone V, Genah S, Morbidelli L. Endothelium as a Source and Target of H 2S to Improve Its Trophism and Function. Antioxidants (Basel) 2021; 10:antiox10030486. [PMID: 33808872 PMCID: PMC8003673 DOI: 10.3390/antiox10030486] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/13/2021] [Accepted: 03/16/2021] [Indexed: 12/18/2022] Open
Abstract
The vascular endothelium consists of a single layer of squamous endothelial cells (ECs) lining the inner surface of blood vessels. Nowadays, it is no longer considered as a simple barrier between the blood and vessel wall, but a central hub to control blood flow homeostasis and fulfill tissue metabolic demands by furnishing oxygen and nutrients. The endothelium regulates the proper functioning of vessels and microcirculation, in terms of tone control, blood fluidity, and fine tuning of inflammatory and redox reactions within the vessel wall and in surrounding tissues. This multiplicity of effects is due to the ability of ECs to produce, process, and release key modulators. Among these, gasotransmitters such as nitric oxide (NO) and hydrogen sulfide (H2S) are very active molecules constitutively produced by endotheliocytes for the maintenance and control of vascular physiological functions, while their impairment is responsible for endothelial dysfunction and cardiovascular disorders such as hypertension, atherosclerosis, and impaired wound healing and vascularization due to diabetes, infections, and ischemia. Upregulation of H2S producing enzymes and administration of H2S donors can be considered as innovative therapeutic approaches to improve EC biology and function, to revert endothelial dysfunction or to prevent cardiovascular disease progression. This review will focus on the beneficial autocrine/paracrine properties of H2S on ECs and the state of the art on H2S potentiating drugs and tools.
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15
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Liao F, Zhu Z, Xiao C, Yuan J, Geng B, Hu J. Hydrogen sulfide inhibits calcium and phosphorus loss after fracture by negatively regulating glucocorticoid/glucocorticoid receptor α. Life Sci 2021; 274:119363. [PMID: 33737083 DOI: 10.1016/j.lfs.2021.119363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/19/2021] [Accepted: 03/11/2021] [Indexed: 11/30/2022]
Abstract
AIMS Post-fracture calcium and phosphorus excretion is greater than influx, which might be caused by stress. Glucocorticoid is known to enhance calcium and phosphorous excretion, and hydrogen sulfide (H2S) has been shown to exert inhibitory effects on glucocorticoid. Therefore, this study explored whether H2S could inhibit calcium and phosphorus loss after fracture by regulating glucocorticoid and/or its receptor. MAIN METHODS The following properties were analyzed in rats with femur fractures: serum and urinary calcium and phosphorus (by colorimetry); bone turnover markers alkaline phosphatase, serum type 1 collagen amino terminal peptide, type 1 procollagen carboxy terminal peptide, and anti-tartaric acid phosphatase (by ELISA); factors related to calcium-phosphorus metabolism including glucocorticoid, parathyroid hormone, calcitonin, fibroblast growth factor 23, and 1,25(OH)2D3 (by ELISA); and sulfhydration of glucocorticoid receptor α in the kidney (by immunoprecipitation linked biotin-switch assay), after supplementing with mifepristone, the H2S donor GYY4137 or H2S generating enzyme inhibitors aminooxyacetic acid and propargylglycine. KEY FINDINGS Serum H2S decreased and glucocorticoid secretion increased in rats post-fracture. The glucocorticoid receptor inhibitor mifepristone partly blunted calcium and phosphorus loss. Furthermore, supplementation with GYY4137 reduced glucocorticoid secretion; inhibited glucocorticoid receptor α activity by sulfhydration; downregulated vitamin D 1α-hydroxylase expression; and upregulated 24-hydroxylase, calbindin-D28k, and sodium phosphate cotransporter 2a expression in the kidney; thereby inhibiting calcium and phosphorus loss induced by fracture. Moreover, inhibiting endogenous H2S generation showed opposite effects. SIGNIFICANCE Our findings suggest that H2S antagonized calcium and phosphorus loss after fracture by reducing glucocorticoid secretion and inhibiting glucocorticoid receptor α activity by sulfhydration.
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Affiliation(s)
- Feng Liao
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Zongdong Zhu
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Chengwei Xiao
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Jiabin Yuan
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Bin Geng
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing 102308, PR China.
| | - Jiang Hu
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China.
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16
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Citi V, Martelli A, Gorica E, Brogi S, Testai L, Calderone V. Role of hydrogen sulfide in endothelial dysfunction: Pathophysiology and therapeutic approaches. J Adv Res 2021; 27:99-113. [PMID: 33318870 PMCID: PMC7728589 DOI: 10.1016/j.jare.2020.05.015] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The vascular endothelium represents a fundamental mechanical and biological barrier for the maintenance of vascular homeostasis along the entire vascular tree. Changes in its integrity are associated to several cardiovascular diseases, including hypertension, atherosclerosis, hyperhomocysteinemia, diabetes, all linked to the peculiar condition named endothelial dysfunction, which is referred to the loss of endothelial physiological functions, comprehending the regulation of vascular relaxation and/or cell redox balance, the inhibition of leukocyte infiltration and the production of NO. Among the endothelium-released vasoactive factors, in the last years hydrogen sulfide has been viewed as one of the main characters involved in the regulation of endothelium functionality, and many studies demonstrated that H2S behaves as a vasoprotective gasotransmitter in those cardiovascular diseases where endothelial dysfunction seems to be the central issue. AIM The role of hydrogen sulfide in endothelial dysfunction-related cardiovascular diseases is discussed in this review. KEY SCIENTIFIC CONCEPTS Possible therapeutic approaches using molecules able to release H2S.
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Affiliation(s)
- Valentina Citi
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Alma Martelli
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Era Gorica
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Simone Brogi
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Lara Testai
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, via Bonanno n.6, 56125 Pisa, Italy
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17
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The effects of sacubitril/valsartan and ramipril on the male fertility in hypertensive rats. North Clin Istanb 2020; 7:425-432. [PMID: 33163876 PMCID: PMC7603857 DOI: 10.14744/nci.2020.30906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 05/29/2020] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE: Renin angiotensinogen system (RAS) inhibitors, ramipril and sacubitril/valsartan are frequently used in the treatment of cardiovascular diseases. Although they are known as contraindicated during pregnancy in hypertensive women, there is not any outcome of their safety in male fertility after exposure to ramipril or sacubitril/valsartan. In this study, we aimed to evaluate the effects of ramipril and sacubitril/valsartan to highlight their safety in the male fertility in normotensive and hypertensive rats. METHODS: Adult male normotensive and dexamethasone-induced hypertensive rats were treated with sacubitril/valsartan, ramipril and saline for 18 days. Arterial blood pressures were verified using carotid artery cannulation. Male fertility parameters, including the testis weights, histopathologic scoring of the testis, sperm count, sperm motility, morphology, and serum testosterone levels, were analyzed in treated and nontreated normotensive/hypertensive rats. RESULTS: Sacubitril/valsartan or ramipril treatments did not reveal a significant difference in sperm production, testicular morphology, and radioimmunoassay of serum testosterone levels compared to the control group. However, sperm motility was significantly reduced in rats under RAS inhibition. CONCLUSION: This finding was likely mediated by the identification of Ang receptors in the tails of rat sperm given that Ang receptors may play a role in the modulation of sperm motility. Identification of RAS-related proteins involved in sperm motility may help to explain their roles in motility. Our data provide general safety evidence for the male fertilization ability after paternal sacubitril/valsartan and ramipril exposure.
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Cui C, Fan J, Zeng Q, Cai J, Chen Y, Chen Z, Wang W, Li SY, Cui Q, Yang J, Tang C, Xu G, Cai J, Geng B. CD4 + T-Cell Endogenous Cystathionine γ Lyase-Hydrogen Sulfide Attenuates Hypertension by Sulfhydrating Liver Kinase B1 to Promote T Regulatory Cell Differentiation and Proliferation. Circulation 2020; 142:1752-1769. [PMID: 32900241 DOI: 10.1161/circulationaha.119.045344] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Hydrogen sulfide (H2S) has antihypertension and anti-inflammatory effects, and its endogenous-generation key enzyme cystathionine γ lyase (CSE) is expressed in CD4+ T cells. However, the role of CD4+ T-cell endogenous CSE/H2S in the development of hypertension is unclear. METHODS Peripheral blood lymphocytes were isolated from hypertensive patients or spontaneously hypertensive rats, then H2S production and expression of its generation enzymes, cystathionine β synthase and CSE, were measured to determine the major H2S generation system changes in hypertension. Mice with CSE-specific knockout in T cells (conditional knockout, by CD4cre mice hybridization) and CD4 null mice were generated for investigating the pathophysiological relevance of the CSE/H2S system. RESULTS In lymphocytes, H2S from CSE, but not cystathionine β synthase, responded to blood pressure changes, supported by lymphocyte CSE protein changes and a negative correlation between H2S production with systolic blood pressure and diastolic blood pressure, but positive correlation with the serum level of interleukin 10 (an anti-inflammatory cytokine). Deletion of CSE in T cells elevated BP (5-8 mm Hg) under the physiological condition and exacerbated angiotensin II-induced hypertension. In keeping with hypertension, mesenteric artery dilation impaired association with arterial inflammation, an effect attributed to reduced immunoinhibitory T regulatory cell (Treg) numbers in the blood and kidney, thus causing excess CD4+ and CD8+ T cell infiltration in perivascular adipose tissues and kidney. CSE knockout CD4+ T cell transfer into CD4 null mice, also showed the similar phenotypes' confirming the role of endogenous CSE/H2S action. Adoptive transfer of Tregs (to conditional knockout mice) reversed hypertension, vascular relaxation impairment, and immunocyte infiltration, which confirmed that conditional knockout-induced hypertension was attributable, in part, to the reduced Treg numbers. Mechanistically, endogenous CSE/H2S promoted Treg differentiation and proliferation by activating AMP-activated protein kinase. In part, it depended on activation of its upstream kinase, liver kinase B1, by sulfhydration to facilitate its substrate binding and phosphorylation. CONCLUSION The constitutive sulfhydration of liver kinase B1 by CSE-derived H2S activates its target kinase, AMP-activated protein kinase, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.
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Affiliation(s)
- Changting Cui
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing, P.R. China (C.C., Z.C., W.W., S.y.L., Jun Cai, B.G.)
| | - Jinghui Fan
- Department of Physiology and Pathophysiology, School of Basic Medical Science; Peking University Health Science Center, Beijing, P.R. China (J.F., Q.C., J.Y., C.T., G.X.)
| | - Qiang Zeng
- Health Management Institute, the Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, P.R. China (Q.Z., Y.C.)
| | - Junyan Cai
- Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu. P.R. China (Junyan Cai)
| | - Yongzeng Chen
- Health Management Institute, the Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, P.R. China (Q.Z., Y.C.)
| | - Zhenzhen Chen
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing, P.R. China (C.C., Z.C., W.W., S.y.L., Jun Cai, B.G.)
| | - Wenjie Wang
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing, P.R. China (C.C., Z.C., W.W., S.y.L., Jun Cai, B.G.)
| | - Shuang Yue Li
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing, P.R. China (C.C., Z.C., W.W., S.y.L., Jun Cai, B.G.)
| | - Qinghua Cui
- Department of Physiology and Pathophysiology, School of Basic Medical Science; Peking University Health Science Center, Beijing, P.R. China (J.F., Q.C., J.Y., C.T., G.X.)
| | - Jichun Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Science; Peking University Health Science Center, Beijing, P.R. China (J.F., Q.C., J.Y., C.T., G.X.)
| | - Chaoshu Tang
- Department of Physiology and Pathophysiology, School of Basic Medical Science; Peking University Health Science Center, Beijing, P.R. China (J.F., Q.C., J.Y., C.T., G.X.)
| | - Guoheng Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Science; Peking University Health Science Center, Beijing, P.R. China (J.F., Q.C., J.Y., C.T., G.X.)
| | - Jun Cai
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing, P.R. China (C.C., Z.C., W.W., S.y.L., Jun Cai, B.G.)
| | - Bin Geng
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing, P.R. China (C.C., Z.C., W.W., S.y.L., Jun Cai, B.G.)
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La Fuente JM, Sevilleja-Ortiz A, García-Rojo E, El Assar M, Fernández A, Pepe-Cardoso AJ, Martínez-Salamanca JI, Romero-Otero J, Rodríguez-Mañas L, Angulo J. Erectile dysfunction is associated with defective L-cysteine/hydrogen sulfide pathway in human corpus cavernosum and penile arteries. Eur J Pharmacol 2020; 884:173370. [PMID: 32712093 DOI: 10.1016/j.ejphar.2020.173370] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 12/24/2022]
Abstract
H2S signaling was proposed to participate in erectile physiology. L-cysteine (CYS)/H2S pathway stimulation causes cGMP-dependent relaxation of human corpus cavernosum (HCC) and penile arteries (HPRA). The aim was to evaluate the impact of ED on CYS/H2S pathway at functional and molecular level in human penile vascular tissues. NaHS- and CYS-induced responses were evaluated in HCC and HPRA from organ donors without ED (NoED, n = 29) and from ED patients undergoing penile prosthesis insertion (n = 45). cGMP accumulation and cystathionine β-synthase and cystathionine γ-lyase expression were also determined. NaHS-induced relaxations were slightly but significantly impaired in HCC but not in HPRA from ED patients. In contrast, CYS-induced relaxations were markedly impaired in HCC (Emax 67.6 ± 4.9% vs 46.2 ± 4.6%, P < 0.01) and HPRA (Emax 80.8 ± 4.0% vs 48.1 ± 8.6%, P < 0.05) from men with ED. Impairment of CYS-induced responses was observed even after separating diabetic ED patients. In HPRA from ED patients, CYS- but not NaHS-induced vasodilation was significantly associated to endothelial function measured as vasodilatory capacity of acetylcholine (ACh) in these preparations (r2 = 0.481, P < 0.01). Impairment of CYS-induced relaxations was related to significant reduction in CYS-induced accumulation of cGMP in cavernosal tissue. Furthermore, the expression of H2S synthesizing enzymes was significantly reduced in HCC from ED patients with respect to NoED. This was confirmed by immunofluorescence in HCC and HPRA sections. ED involves impairment of CYS/H2S pathway in penile vascular tissues associated with decreased expression of H2S generating enzymes, CBS and CSE. These evidences support a therapeutic potential for modulation of CYS/H2S signaling in the management of ED.
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Affiliation(s)
| | | | - Esther García-Rojo
- Servicio de Urología, Hospital Universitario Doce de Octubre, Madrid, Spain
| | | | - Argentina Fernández
- Servicio de Histología-Investigación, Hospital Universitario Ramón y Cajal - IRYCIS, Madrid, Spain
| | | | | | | | | | - Javier Angulo
- Servicio de Histología-Investigación, Hospital Universitario Ramón y Cajal - IRYCIS, Madrid, Spain.
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20
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Chen Y, Zhang F, Yin J, Wu S, Zhou X. Protective mechanisms of hydrogen sulfide in myocardial ischemia. J Cell Physiol 2020; 235:9059-9070. [PMID: 32542668 DOI: 10.1002/jcp.29761] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 04/09/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023]
Abstract
Hydrogen sulfide (H2 S), which has been identified as the third gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO), plays an important role in maintaining homeostasis in the cardiovascular system. Endogenous H2 S is produced mainly by three endogenous enzymes: cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfur transferase. Numerous studies have shown that H2 S has a significant protective role in myocardial ischemia. The mechanisms by which H2 S affords cardioprotection include the antifibrotic and antiapoptotic effects, regulation of ion channels, protection of mitochondria, reduction of oxidative stress and inflammatory response, regulation of microRNA expression, and promotion of angiogenesis. Amplification of NO- and CO-mediated signaling through crosstalk between H2 S, NO, and CO may also contribute to the cardioprotective effect. Exogenous H2 S donors are expected to become effective drugs for the treatment of cardiovascular diseases. This review article focuses on the protective mechanisms and potential therapeutic applications of H2 S in myocardial ischemia.
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Affiliation(s)
- Yuqi Chen
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Feng Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China
| | - Jiayu Yin
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Siyi Wu
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiang Zhou
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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21
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Sun HJ, Wu ZY, Nie XW, Bian JS. Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide. Front Pharmacol 2020; 10:1568. [PMID: 32038245 PMCID: PMC6985156 DOI: 10.3389/fphar.2019.01568] [Citation(s) in RCA: 340] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022] Open
Abstract
Endothelial cells are important constituents of blood vessels that play critical roles in cardiovascular homeostasis by regulating blood fluidity and fibrinolysis, vascular tone, angiogenesis, monocyte/leukocyte adhesion, and platelet aggregation. The normal vascular endothelium is taken as a gatekeeper of cardiovascular health, whereas abnormality of vascular endothelium is a major contributor to a plethora of cardiovascular ailments, such as atherosclerosis, aging, hypertension, obesity, and diabetes. Endothelial dysfunction is characterized by imbalanced vasodilation and vasoconstriction, elevated reactive oxygen species (ROS), and proinflammatory factors, as well as deficiency of nitric oxide (NO) bioavailability. The occurrence of endothelial dysfunction disrupts the endothelial barrier permeability that is a part of inflammatory response in the development of cardiovascular diseases. As such, abrogation of endothelial cell activation/inflammation is of clinical relevance. Recently, hydrogen sulfide (H2S), an entry as a gasotransmitter, exerts diverse biological effects through acting on various targeted signaling pathways. Within the cardiovascular system, the formation of H2S is detected in smooth muscle cells, vascular endothelial cells, and cardiomyocytes. Disrupted H2S bioavailability is postulated to be a new indicator for endothelial cell inflammation and its associated endothelial dysfunction. In this review, we will summarize recent advances about the roles of H2S in endothelial cell homeostasis, especially under pathological conditions, and discuss its putative therapeutic applications in endothelial inflammation-associated cardiovascular disorders.
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Affiliation(s)
- Hai-Jian Sun
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Zhi-Yuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xiao-Wei Nie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,National University of Singapore (Suzhou) Research Institute, Suzhou, China
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22
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Nagahara N, Tanaka M, Tanaka Y, Ito T. Novel Characterization of Antioxidant Enzyme, 3-Mercaptopyruvate Sulfurtransferase-Knockout Mice: Overexpression of the Evolutionarily-Related Enzyme Rhodanese. Antioxidants (Basel) 2019; 8:antiox8050116. [PMID: 31052467 PMCID: PMC6562775 DOI: 10.3390/antiox8050116] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 04/24/2019] [Accepted: 04/26/2019] [Indexed: 11/22/2022] Open
Abstract
The antioxidant enzyme, 3-mercaptopyruvate sulfurtransferase (MST, EC 2.8.1.2) is localized in the cytosol and mitochondria, while the evolutionarily-related enzyme, rhodanese (thiosulfate sulfurtransferase, TST, EC 2.8.1.1) is localized in the mitochondria. Recently, both enzymes have been shown to produce hydrogen sulfide and polysulfide. Subcellular fractionation of liver mitochondria revealed that the TST activity ratio of MST-knockout (KO)/wild-type mice was approximately 2.5; MST activity was detected only in wild-type mice, as expected. The ratio of TST mRNA expression of KO/wild-type mice, as measured by real-time quantitative polymerase chain reaction analysis, was approximately 3.3. It is concluded that TST is overexpressed in MST-KO mice.
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Affiliation(s)
- Noriyuki Nagahara
- Isotope Research Laboratory, Nippon Medical School, Tokyo 113-8602, Japan.
| | - Mio Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.
| | - Yukichi Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.
| | - Takaaki Ito
- Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan.
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Endogenous CSE/Hydrogen Sulfide System Regulates the Effects of Glucocorticoids and Insulin on Muscle Protein Synthesis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9752698. [PMID: 31089421 PMCID: PMC6476024 DOI: 10.1155/2019/9752698] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/09/2018] [Accepted: 12/18/2018] [Indexed: 01/25/2023]
Abstract
Aims Insulin and glucocorticoids play crucial roles in skeletal muscle protein turnover. Fast-twitch glycolytic fibres are more susceptible to atrophy than slow-twitch oxidative fibres. Based on accumulating evidence, hydrogen sulfide (H2S) is a physiological mediator of this process. The regulatory effect of H2S on protein synthesis in fast-twitch fibres was evaluated. Results A NaHS (sodium hydrosulfide) injection simultaneously increased the diameter of M. pectoralis major (i.e., fast-twitch glycolytic fibres) and activated the mammalian target of the rapamycin (mTOR)/p70S6 kinase (p70S6K) pathway. Dexamethasone (DEX) inhibited protein synthesis, downregulated mTOR and p70S6K phosphorylation, and suppressed the expression of the cystathionine γ-lyase (CSE) protein in myoblasts. The precursor of H2S, L-cysteine, completely abolished the inhibitory effects of DEX. The CSE inhibitor DL-propargylglycine (PAG) completely abrogated the effects of RU486 on blocking the suppressive effects of DEX. The H2S donor NaHS increased the H2S concentrations and abrogated the inhibitory effects of DEX on protein synthesis. Insulin increased protein synthesis and upregulated CSE expression. However, PAG abrogated the stimulatory effects of insulin on protein synthesis and the activity of the mTOR/p70S6K pathway. Innovation These results demonstrated that CSE/H2S regulated protein synthesis in fast-twitch muscle fibres, and glucocorticoids and insulin regulated protein synthesis in an endogenous CSE/H2S system-dependent manner. Conclusions The results from the present study suggest that the endogenous CSE/H2S system regulates fast-twitch glycolytic muscle degeneration and regeneration.
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Bitar MS, Nader J, Al-Ali W, Al Madhoun A, Arefanian H, Al-Mulla F. Hydrogen Sulfide Donor NaHS Improves Metabolism and Reduces Muscle Atrophy in Type 2 Diabetes: Implication for Understanding Sarcopenic Pathophysiology. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6825452. [PMID: 30510624 PMCID: PMC6232794 DOI: 10.1155/2018/6825452] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 08/09/2018] [Accepted: 08/15/2018] [Indexed: 12/15/2022]
Abstract
Sarcopenia, a loss of muscle mass and functionality, constitutes a major contributor to disability in diabetes. Hydrogen sulfide (H2S) dynamics and muscle mass regulatory signaling were studied in GK rats, a model for type 2 diabetes (T2D). GK rats exhibited a number of features that are consistent with sarcopenia and T2D including loss of muscle mass and strength, in addition to glucose intolerance, insulin resistance, and impaired β-cell responsiveness to glucose. Mechanistically, activation levels of Akt, a key modulator of protein balance, were decreased in T2D. Consequently, we confirmed reduced activity of mTOR signaling components and higher expression of atrophy-related markers typified by FoxO1/atrogin-1/MuRF1 and myostatin-Smad2/3 signaling during the course of diabetes. We observed in GK rat reduced antioxidant capacity (↓GSH/GSSG) and increased expression and activity of NADPH oxidase in connection with augmented rate of oxidation of lipids, proteins, and DNA. H2S bioavailability and the expression of key enzymes involved in its synthesis were suppressed as a function of diabetes. Interestingly, GK rats receiving NaHS displayed increased muscle Akt/mTOR signaling and decreased expression of myostatin and the FoxO1/MuRF1/atrogin-dependent pathway. Moreover, diabetes-induced heightened state of oxidative stress was also ameliorated in response to NaHS therapy. Overall, the current data support the notion that a relationship exists between sarcopenia, heightened state of oxidative stress, and H2S deficiency at least in the context of diabetes. Moreover, treatment with a potent H2S donor at an early stage of diabetes is likely to mitigate the development of sarcopenia/frailty and predictably reduces its devastating sequelae of amputation.
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Affiliation(s)
- Milad S. Bitar
- Department of Pharmacology & Toxicology, Kuwait University, Faculty of Medicine, Kuwait
- Immunology Unit, Dasman Diabetes Institute, Kuwait
| | - Joelle Nader
- Department of Mathematics & Natural Sciences, American University of Kuwait, Kuwait
| | - Waleed Al-Ali
- Department of Pathology, Kuwait University, Faculty of Medicine, Kuwait
| | | | | | - Fahd Al-Mulla
- Functional Genomics Unit, Dasman Diabetes Institute, Kuwait
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25
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Abstract
Cyclosporine A (CsA) induces hypertension after transplantation. Hydrogen sulfide (H2S) was found to have hypotensive/vasoprotective effects in the cardiovascular system. The present study aims to investigate the role of H2S on CsA-induced vascular function disorder in rats. Rats were subcutaneously injected with CsA 25 mg/kg for 21 days. Blood pressure was measured by the tail-cuff method. Vasomotion was determined using a sensitive myograph. Western blotting and immunohistochemistry were used to quantify the protein expression of endothelin type A (ETA) receptor and essential MAPK pathway molecules. Vascular superoxide anion production and serum contents of malondialdehyde were determined. The results showed that sodium hydrosulfide (NaHS), a H2S donor, significantly attenuated the increase of blood pressure and contractile responses, and the upregulation of ETA receptor induced by CsA. In addition, NaHS could restore the CsA decreased acetylcholine-induced vasodilatation. Furthermore, NaHS blocked the CsA-induced elevation of reactive oxygen species level, extracellular signal-regulated kinase and p38 MAPK activities. In conclusion, H2S prevents CsA-induced vasomotor dysfunction. H2S attenuates CsA-induced ETA receptor upregulation, which may be associated with MAPK signal pathways. H2S ameliorates endothelial-dependent relaxation, which may be through antioxidant activity.
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26
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Hydrogen sulfide as a regulatory factor in kidney health and disease. Biochem Pharmacol 2018; 149:29-41. [DOI: 10.1016/j.bcp.2017.12.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 12/05/2017] [Indexed: 12/19/2022]
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27
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Mercaptopyruvate acts as endogenous vasodilator independently of 3-mercaptopyruvate sulfurtransferase activity. Nitric Oxide 2018; 75:53-59. [PMID: 29452248 DOI: 10.1016/j.niox.2018.02.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 01/30/2018] [Accepted: 02/12/2018] [Indexed: 12/16/2022]
Abstract
Hydrogen sulfide (H2S) is produced by the action of cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) or 3-mercaptopyruvate sulfurtransferase (3-MST). 3-MST converts 3-mercaptopyruvate (MPT) to H2S and pyruvate. H2S is recognized as an endogenous gaseous mediator with multiple regulatory roles in mammalian cells and organisms. In the present study we demonstrate that MPT, the endogenous substrate of 3-MST, acts also as endogenous H2S donor. Colorimetric, amperometric and fluorescence based assays demonstrated that MPT releases H2S in vitro in an enzyme-independent manner. A functional study was performed on aortic rings harvested from C57BL/6 (WT) or 3-MST-knockout (3-MST-/-) mice with and without endothelium. MPT relaxed mouse aortic rings in endothelium-independent manner and at the same extent in both WT and 3-MST-/- mice. N5-(1-Iminoethyl)-l-ornithine dihydrochloride (L-NIO, an inhibitor of endothelial nitric oxide synthase) as well as 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) did not affect MPT relaxant action. Conversely, hemoglobin (as H2S scavenger), as well as glybenclamide (an ATP-dependent potassium channel blocker) markedly reduced MPT-induced relaxation. The functional data clearly confirmed a non enzymatic vascular effect of MPT. In conclusion, MPT acts also as an endogenous H2S donor and not only as 3-MST substrate. MPT could, thus, be further investigated as a means to increase H2S in conditions where H2S bioavailability is reduced such as hypertension, coronary artery disease, diabetes or urogenital tract disease.
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28
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Szabo C, Papapetropoulos A. International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H 2S Levels: H 2S Donors and H 2S Biosynthesis Inhibitors. Pharmacol Rev 2017; 69:497-564. [PMID: 28978633 PMCID: PMC5629631 DOI: 10.1124/pr.117.014050] [Citation(s) in RCA: 304] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition of H2S biosynthesis. H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasing H2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, an H2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
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Affiliation(s)
- Csaba Szabo
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas (C.S.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece (A.P.); and Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.)
| | - Andreas Papapetropoulos
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas (C.S.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece (A.P.); and Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.)
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29
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Yuan S, Shen X, Kevil CG. Beyond a Gasotransmitter: Hydrogen Sulfide and Polysulfide in Cardiovascular Health and Immune Response. Antioxid Redox Signal 2017; 27:634-653. [PMID: 28398086 PMCID: PMC5576200 DOI: 10.1089/ars.2017.7096] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
SIGNIFICANCE Hydrogen sulfide (H2S) metabolism leads to the formation of oxidized sulfide species, including polysulfide, persulfide, and others. Evidence is emerging that many biological effects of H2S may indeed be due to polysulfide and persulfide activation of signaling pathways and reactivity with discrete small molecules. Recent Advances: Exogenous oxidized sulfide species, including polysulfides, are more reactive than H2S with a wide range of molecules. Importantly, endogenous polysulfide and persulfide formation has been reported to occur via transsulfuration enzymes, cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS). CRITICAL ISSUES In light of the recent understanding of oxidized sulfide metabolite formation and reactivity, comparatively few studies have been reported comparing cellular biological and in vivo effects of H2S donors versus polysulfide and persulfide donors. Likewise, it is equally unclear when, how, and to what extent persulfide and polysulfide formation occurs in vivo under pathophysiological conditions. FUTURE DIRECTIONS Additional studies regarding persulfide and polysulfide formation and molecular reactions are needed in nearly all aspects of biology to better understand how sulfide metabolites contribute to key chemical biology reactions involved in cardiovascular health and immune responses. Antioxid. Redox Signal. 27, 634-653.
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Affiliation(s)
- Shuai Yuan
- 1 Department of Cell Biology and Anatomy, LSU Health Sciences Center Shreveport , Shreveport, Louisiana
| | - Xinggui Shen
- 2 Department of Pathology and Translational Pathobiology, LSU Health Sciences Center Shreveport , Shreveport, Louisiana
| | - Christopher G Kevil
- 2 Department of Pathology and Translational Pathobiology, LSU Health Sciences Center Shreveport , Shreveport, Louisiana
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Tian D, Dong J, Jin S, Teng X, Wu Y. Endogenous hydrogen sulfide-mediated MAPK inhibition preserves endothelial function through TXNIP signaling. Free Radic Biol Med 2017; 110:291-299. [PMID: 28669627 DOI: 10.1016/j.freeradbiomed.2017.06.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 06/03/2017] [Accepted: 06/26/2017] [Indexed: 12/20/2022]
Abstract
Mounting evidence demonstrated deficient cystathionine-γ-lyase (CSE)/H2S implicated the development of cardiovascular disease. The present study aimed to evaluating the favorable action of CSE derived H2S on endothelial function in CSE-/- mice. CSE-/- mice exhibited attenuated endothelium-dependent relaxations, coupled with reduction of endothelial nitric oxide synthase (eNOS) phosphorylation at site of Ser1177, increase of thioredoxin interacting protein (TXNIP) level and MAPK phosphorylation, which were corrected by sodium hydrosulfide chronic treatment for 8 weeks. Impaired relaxations to ACh and upregulated TXNIP of CSE-/- mice aorta were partially corrected by p38 inhibitor, extracellular regulated protein kinase (ERK) inhibitor and c-Jun N-terminal kinase (JNK) inhibitor and totally corrected by combined treatment. Pharmacological inhibition of CSE with DL-propargylglycine (PPG) in vivo and ex vivo induced endothelial dysfunction. PPG stimulated the phosphorylation of p38, JNK and ERK in human umbilical vein endothelial cells (HUVECs). MAPK inhibition by combined treatment of p38, JNK and ERK inhibitors normalized the endothelial changes of eNOS phosphorylation and TXNIP protein level in CSE-/- mice aorta and PPG-treated HUVECs. NaHS offered similar effect with MAKP inhibitors. TXNIP siRNA prevented against endothelial function by PPG and TXNIP overexpression mimics the detrimental effect of PPG treatment on endothelial function, whereas MAPK inhibitor or NaHS has no beneficial effect. In a word, Endogenous CSE/H2S benefits against endothelial dysfunction through suppressing MAPK/TXNIP cascade. CSE deficiency and consequently lowered endogenous H2S level should be considered as risk factors and biomarkers for endothelial dysfunction.
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Affiliation(s)
- Danyang Tian
- Department of Physiology, Hebei Medical University, Shijiazhuang, China
| | - Jinghui Dong
- Department of Physiology, Hebei Medical University, Shijiazhuang, China
| | - Sheng Jin
- Department of Physiology, Hebei Medical University, Shijiazhuang, China
| | - Xu Teng
- Department of Physiology, Hebei Medical University, Shijiazhuang, China
| | - Yuming Wu
- Department of Physiology, Hebei Medical University, Shijiazhuang, China; Hebei Collaborative Innovation Center for Cardio-Cerebrovascular Disease, Shijiazhuang 050017, China.
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31
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Ertuna E, Loot AE, Fleming I, Yetik-Anacak G. The role of eNOS on the compensatory regulation of vascular tonus by H 2 S in mouse carotid arteries. Nitric Oxide 2017; 69:45-50. [DOI: 10.1016/j.niox.2017.04.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 03/06/2017] [Accepted: 04/12/2017] [Indexed: 11/30/2022]
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32
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Aydinoglu F, Ogulener N. The role of arachidonic acid/cyclooxygenase cascade, phosphodiesterase IV and Rho-kinase in H 2 S-induced relaxation in the mouse corpus cavernosum. Pharmacol Rep 2017; 69:610-615. [DOI: 10.1016/j.pharep.2017.02.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 01/10/2017] [Accepted: 02/22/2017] [Indexed: 12/19/2022]
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β 3 adrenergic receptor activation relaxes human corpus cavernosum and penile artery through a hydrogen sulfide/cGMP-dependent mechanism. Pharmacol Res 2017; 124:100-104. [PMID: 28760490 DOI: 10.1016/j.phrs.2017.07.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 07/25/2017] [Accepted: 07/27/2017] [Indexed: 12/21/2022]
Abstract
Erectile function is a widely accepted indicator of systemic endothelial activity since from a clinical standpoint erectile dysfunction (ED) often precedes cardiovascular events. Recently it has been described a potential role for β3 adrenoceptor in cardiovascular diseases emphasizing a possible development of new drugs. β3 adrenoceptor stimulation relaxes human corpus cavernosum (HCC) strips in cyclic guanosine monophosphate (cGMP)-dependent and endothelium/nitric oxide (NO)-independent manner. Hydrogen sulfide (H2S), along with NO, is another gaseous molecule involved in cardiovascular system and as a consequence also in penile erection. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), the enzymes mainly responsible for H2S biosynthesis, are constitutively expressed in HCC. CSE rather than CBS is more abundant in human penile tissue. Herein we investigated the involvement of H2S pathway in β3 adrenoceptor-induced relaxation in HCC and penile artery. Penile artery expresses both CSE and β3 adrenoceptor. BRL37344, a β3 selective agonist, relaxed HCC strips and penile artery rings and this effect was significantly reduced by CSE inhibition. Incubation of HCC and penile artery homogenate with BRL37344 significantly increased H2S production. This effect was significantly reduced by the inhibition of either CSE or β3 adrenoceptor. Finally, the BRL37344-induced increase in cGMP was reduced by CSE inhibition in both tissues. Thus, BRL37344-induced relaxation in HCC and penile artery occurs in a H2S/cGMP-dependent manner. In conclusion, β3/H2S/cGMP pathway can act as an alternative to NO. Since about 15% of patients do not respond to phosphodiesterase-5 inhibitors, β3 agonists could represent a therapeutic alternative or a useful adjuvant therapy to treat these patients.
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Tan XX, Lian KQ, Li X, Li N, Wang W, Kang WJ, Shi HM. Development of a derivatization method for the quantification of hydrogen sulfide and its application in vascular calcification rats. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1055-1056:8-14. [DOI: 10.1016/j.jchromb.2017.04.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Revised: 02/28/2017] [Accepted: 04/12/2017] [Indexed: 01/27/2023]
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Kanagy NL, Szabo C, Papapetropoulos A. Vascular biology of hydrogen sulfide. Am J Physiol Cell Physiol 2017; 312:C537-C549. [PMID: 28148499 PMCID: PMC5451519 DOI: 10.1152/ajpcell.00329.2016] [Citation(s) in RCA: 157] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/24/2017] [Accepted: 01/27/2017] [Indexed: 12/23/2022]
Abstract
Hydrogen sulfide (H2S) is a ubiquitous signaling molecule with important functions in many mammalian organs and systems. Observations in the 1990s ascribed physiological actions to H2S in the nervous system, proposing that this gasotransmitter acts as a neuromodulator. Soon after that, the vasodilating properties of H2S were demonstrated. In the past decade, H2S was shown to exert a multitude of physiological effects in the vessel wall. H2S is produced by vascular cells and exhibits antioxidant, antiapoptotic, anti-inflammatory, and vasoactive properties. In this concise review, we have focused on the impact of H2S on vascular structure and function with an emphasis on angiogenesis, vascular tone, vascular permeability and atherosclerosis. H2S reduces arterial blood pressure, limits atheromatous plaque formation, and promotes vascularization of ischemic tissues. Although the beneficial properties of H2S are well established, mechanistic insights into the molecular pathways implicated in disease prevention and treatment remain largely unexplored. Unraveling the targets and downstream effectors of H2S in the vessel wall in the context of disease will aid in translation of preclinical observations. In addition, acute regulation of H2S production is still poorly understood and additional work delineating the pathways regulating the enzymes that produce H2S will allow pharmacological manipulation of this pathway. As the field continues to grow, we expect that H2S-related compounds will find their way into clinical trials for diseases affecting the blood vessels.
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Affiliation(s)
- Nancy L Kanagy
- Vascular Physiology Group, Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, New Mexico
| | - Csaba Szabo
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas
| | - Andreas Papapetropoulos
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece; and
- Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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Greaney JL, Kutz JL, Shank SW, Jandu S, Santhanam L, Alexander LM. Impaired Hydrogen Sulfide-Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults. Hypertension 2017; 69:902-909. [PMID: 28348008 DOI: 10.1161/hypertensionaha.116.08964] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 01/03/2017] [Accepted: 02/17/2017] [Indexed: 12/22/2022]
Abstract
Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10-6-10-1 mol/L) and sodium sulfide (10-5-101 mol/L) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all P<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN adults (P=0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg; P=0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg; P=0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension.
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Affiliation(s)
- Jody L Greaney
- From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.)
| | - Jessica L Kutz
- From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.)
| | - Sean W Shank
- From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.)
| | - Sandeep Jandu
- From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.)
| | - Lakshmi Santhanam
- From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.)
| | - Lacy M Alexander
- From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.).
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Donnarumma E, Trivedi RK, Lefer DJ. Protective Actions of H2S in Acute Myocardial Infarction and Heart Failure. Compr Physiol 2017; 7:583-602. [PMID: 28333381 DOI: 10.1002/cphy.c160023] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hydrogen sulfide (H2S) was identified as the third gasotransmitter in 1996 following the discoveries of the biological importance of nitric oxide and carbon monoxide. Although H2S has long been considered a highly toxic gas, the discovery of its presence and enzymatic production in mammalian tissues supports a critical role for this physiological signaling molecule. H2S is synthesized endogenously by three enzymes: cystathionine β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. H2S plays a pivotal role in the regulation of cardiovascular function as H2S has been shown to modulate: vasodilation, angiogenesis, inflammation, oxidative stress, and apoptosis. Perturbation of endogenous production of H2S has been associated with many pathological conditions of the cardiovascular system such as diabetes, heart failure, and hypertension. As such, modulation of the endogenous H2S signaling pathway or administration of exogenous H2S has been shown to be cytoprotective. This review article will provide a summary of the current body of evidence on the role of H2S signaling in the setting of myocardial ischemia and heart failure. © 2017 American Physiological Society. Compr Physiol 7:583-602, 2017.
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Affiliation(s)
- Erminia Donnarumma
- Cardiovascular Center of Excellence Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Rishi K Trivedi
- Cardiovascular Center of Excellence Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - David J Lefer
- Cardiovascular Center of Excellence Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
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Yang X, Hao D, Zhang H, Liu B, Yang M, He B. Treatment with hydrogen sulfide attenuates sublesional skeletal deterioration following motor complete spinal cord injury in rats. Osteoporos Int 2017; 28:687-695. [PMID: 27591786 DOI: 10.1007/s00198-016-3756-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Accepted: 08/23/2016] [Indexed: 11/28/2022]
Abstract
UNLABELLED Treatment with hydrogen sulfide mitigates spinal cord injury-induced sublesional bone loss, possibly through abating oxidative stress, suppressing MMP activity, and activating Wnt/β-catenin signaling. INTRODUCTION Spinal cord injury (SCI)-induced sublesional bone loss represents the most severe osteoporosis and is resistant to available treatments to data. The present study was undertaken to explore the therapeutic potential of hydrogen sulfide (H2S) against osteoporosis in a rodent model of motor complete SCI. METHODS SCI was generated by surgical transaction of the cord at the T3-T4 levels in rats. Treatment with NaHS was initiated through intraperitoneal injection of 0.1 ml/kg/day of 0.28 mol/l NaHS from 12 h following the surgery and over 14 subsequent days. RESULTS H2S levels in plasma of SCI rats were lower, which was restored by treatment with exogenous H2S. Treatment of SCI rats with exogenous H2S had no significant effect on body mass but increased bone mineral density in femurs and tibiae, increased BV/TV, Tb.Th, and Tb.N and reduced Tb.Sp in proximal tibiae, and increased mineral apposition rate (MAR), bone formation rate (BFR), and osteoblast surface and reduced eroded surface and osteoclast surface in proximal tibiae. More importantly, H2S treatment led to a significant enhancement in ultimate load, stiffness, and energy to max force of femoral diaphysis. Treatment of SCI rats with exogenous H2S reduced malondialdehyde (MDA) levels in serum and femurs, decreased hydroxyproline levels, suppressed activities of matrix metallopeptidase 9 (MMP9), and upregulated Wnt3a, Wnt6, Wnt10, and ctnnb1 expression in femurs. CONCLUSION Treatment with H2S mitigates SCI-induced sublesional bone loss, possibly through abating oxidative stress, suppressing MMP activity, and activating Wnt/β-catenin signaling.
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Affiliation(s)
- X Yang
- Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Youyi East Road 555, Xi'an, 710054, China
| | - D Hao
- Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Youyi East Road 555, Xi'an, 710054, China
| | - H Zhang
- Diagnostic Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, 710054, China
| | - B Liu
- Diagnostic Center, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, 710054, China
| | - M Yang
- Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Youyi East Road 555, Xi'an, 710054, China
| | - B He
- Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Youyi East Road 555, Xi'an, 710054, China.
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H 2S as a possible therapeutic alternative for the treatment of hypertensive kidney injury. Nitric Oxide 2017; 64:52-60. [PMID: 28069557 DOI: 10.1016/j.niox.2017.01.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 12/22/2016] [Accepted: 01/04/2017] [Indexed: 12/12/2022]
Abstract
Hypertension is the most common cause of cardiovascular morbidities and mortalities, and a major risk factor for renal dysfunction. It is considered one of the causes of chronic kidney disease, which progresses into end-stage renal disease and eventually loss of renal function. Yet, the mechanism underlying the pathogenesis of hypertension and its associated kidney injury is still poorly understood. Moreover, despite existing antihypertensive therapies, achievement of blood pressure control and preservation of renal function still remain a worldwide public health challenge in a subset of hypertensive patients. Therefore, novel modes of intervention are in demand. Hydrogen sulfide (H2S), a gaseous signaling molecule, has been established to possess antihypertensive and renoprotective properties, which may represent an important therapeutic alternative for the treatment of hypertension and kidney injury. This review discusses recent findings about H2S in hypertension and kidney injury from both experimental and clinical studies. It also addresses future direction regarding therapeutic use of H2S.
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Abstract
SIGNIFICANCE Hydrogen sulfide (H2S) has only recently gained recognition for its physiological effects. It is synthesized widely in the mammalian tissues and regulates several biologic processes ranging from development, angiogenesis, neurotransmission to protein synthesis. Recent Advances: The aim of this review is to critically evaluate the evidence for a role for H2S in kidney function and disease. CRITICAL ISSUES H2S regulates fundamental kidney physiologic processes such as glomerular filtration and sodium reabsorption. In kidney disease states H2S appears to play a complex role in a context-dependent manner. In some disease states such as ischemia-reperfusion and diabetic kidney disease it can serve as an agent that ameliorates kidney injury. In other diseases such as cis-platinum-induced kidney disease it may mediate kidney injury although more investigation is needed. Recent studies have revealed that the actions of nitric oxide and H2S may be integrated in kidney cells. FUTURE DIRECTIONS Further studies are needed to understand the full impact of H2S on kidney physiology. As it is endowed with the properties of regulating blood flow, oxidative stress, and inflammation, H2S should be investigated for its role in inflammatory and toxic diseases of the kidney. Such in-depth exploration may identify specific kidney diseases in which H2S may constitute a unique target for therapeutic intervention. Antioxid. Redox Signal. 25, 720-731.
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Affiliation(s)
- Denis Feliers
- 1 Division of Nephrology, Department of Medicine, University of Texas Health Science Center , San Antonio, Texas
| | - Hak Joo Lee
- 1 Division of Nephrology, Department of Medicine, University of Texas Health Science Center , San Antonio, Texas.,2 South Texas Veterans Healthcare System , San Antonio, Texas
| | - Balakuntalam S Kasinath
- 1 Division of Nephrology, Department of Medicine, University of Texas Health Science Center , San Antonio, Texas.,2 South Texas Veterans Healthcare System , San Antonio, Texas
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d’Emmanuele di Villa Bianca R, Mitidieri E, Fusco F, Russo A, Pagliara V, Tramontano T, Donnarumma E, Mirone V, Cirino G, Russo G, Sorrentino R. Urothelium muscarinic activation phosphorylates CBS(Ser227) via cGMP/PKG pathway causing human bladder relaxation through H2S production. Sci Rep 2016; 6:31491. [PMID: 27509878 PMCID: PMC4980605 DOI: 10.1038/srep31491] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 07/20/2016] [Indexed: 12/18/2022] Open
Abstract
The urothelium modulates detrusor activity through releasing factors whose nature has not been clearly defined. Here we have investigated the involvement of H2S as possible mediator released downstream following muscarinic (M) activation, by using human bladder and urothelial T24 cell line. Carbachol stimulation enhances H2S production and in turn cGMP in human urothelium or in T24 cells. This effect is reversed by cysthationine-β-synthase (CBS) inhibition. The blockade of M1 and M3 receptors reverses the increase in H2S production in human urothelium. In T24 cells, the blockade of M1 receptor significantly reduces carbachol-induced H2S production. In the functional studies, the urothelium removal from human bladder strips leads to an increase in carbachol-induced contraction that is mimicked by CBS inhibition. Instead, the CSE blockade does not significantly affect carbachol-induced contraction. The increase in H2S production and in turn of cGMP is driven by CBS-cGMP/PKG-dependent phosphorylation at Ser(227) following carbachol stimulation. The finding of the presence of this crosstalk between the cGMP/PKG and H2S pathway downstream to the M1/M3 receptor in the human urothelium further implies a key role for H2S in bladder physiopathology. Thus, the modulation of the H2S pathway can represent a feasible therapeutic target to develop drugs for bladder disorders.
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Affiliation(s)
- Roberta d’Emmanuele di Villa Bianca
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy
| | - Emma Mitidieri
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | - Ferdinando Fusco
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy
- Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples, Federico II, Naples, 80131, Italy
| | - Annapina Russo
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | - Valentina Pagliara
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | - Teresa Tramontano
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | - Erminia Donnarumma
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | - Vincenzo Mirone
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy
- Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples, Federico II, Naples, 80131, Italy
| | - Giuseppe Cirino
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy
| | - Giulia Russo
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | - Raffaella Sorrentino
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy
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Mitidieri E, Tramontano T, Donnarumma E, Brancaleone V, Cirino G, D Emmanuele di Villa Bianca R, Sorrentino R. l-Cys/CSE/H2S pathway modulates mouse uterus motility and sildenafil effect. Pharmacol Res 2016; 111:283-289. [PMID: 27326921 DOI: 10.1016/j.phrs.2016.06.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 06/15/2016] [Accepted: 06/16/2016] [Indexed: 10/21/2022]
Abstract
Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, commonly used in the oral treatment for erectile dysfunction, relaxes smooth muscle of human bladder through the activation of hydrogen sulfide (H2S) signaling. H2S is an endogenous gaseous transmitter with myorelaxant properties predominantly formed from l-cysteine (l-Cys) by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Sildenafil also relaxes rat and human myometrium during preterm labor but the underlying mechanism is still unclear. In the present study we investigated the possible involvement of H2S as a mediator of sildenafil-induced effect in uterine mouse contractility. We firstly demonstrated that both enzymes, CBS and CSE were expressed, and able to convert l-Cys into H2S in mouse uterus. Thereafter, sildenafil significantly increased H2S production in mouse uterus and this effect was abrogated by CBS or CSE inhibition. In parallel, l-Cys, sodium hydrogen sulfide or sildenafil but not d-Cys reduced spontaneous uterus contractility in a functional study. The blockage of CBS and CSE reduced this latter effect even if a major role for CSE than CBS was observed. This data was strongly confirmed by using CSE(-/-) mice. Indeed, the increase in H2S production mediated by l-Cys or by sildenafil was not found in CSE(-/-) mice. Besides, the effect of H2S or sildenafil on spontaneous contractility was reduced in CSE(-/-) mice. A decisive proof for the involvement of H2S signaling in sildenafil effect in mice uterus was given by the measurement of cGMP. Sildenafil increased cGMP level that was significantly reduced by CSE inhibition. In conclusion, l-Cys/CSE/H2S signaling modulates the mouse uterus motility and the sildenafil effect. Therefore the study may open different therapeutical approaches for the management of the uterus abnormal contractility disorders.
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Affiliation(s)
- Emma Mitidieri
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | - Teresa Tramontano
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | - Erminia Donnarumma
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | - Vincenzo Brancaleone
- Department of Science, University of Basilicata, Via dell⿿Ateneo Lucano, 85100 Potenza, Italy
| | - Giuseppe Cirino
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy
| | | | - Raffaella Sorrentino
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
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Abstract
In recent years, it has become apparent that the gaseous pollutant, hydrogen sulphide (H2S) can be synthesised in the body and has a multitude of biological actions. This review summarizes some of the actions of this 'gasotransmitter' in influencing the smooth muscle that is responsible for controlling muscular activity of hollow organs. In the vasculature, while H2S can cause vasoconstriction by complex interactions with other biologically important gases, such as nitric oxide, the prevailing response is vasorelaxation. While most vasorelaxation responses occur by a direct action of H2S on smooth muscle cells, it has recently been proposed to be an endothelium-derived hyperpolarizing factor. H2S also promotes relaxation in other smooth muscle preparations including bronchioles, the bladder, gastrointestinal tract and myometrium, opening up the opportunity of exploiting the pharmacology of H2S in the treatment of conditions where smooth muscle tone is excessive. The original concept, that H2S caused smooth muscle relaxation by activating ATP-sensitive K(+) channels, has been supplemented with observations that H2S can also modify the activity of other potassium channels, intracellular pH, phosphodiesterase activity and transient receptor potential channels on sensory nerves. While the enzymes responsible for generating endogenous H2S are widely expressed in smooth muscle preparations, it is much less clear what the physiological role of H2S is in determining smooth muscle contractility. Clarification of this requires the development of potent and selective inhibitors of H2S-generating enzymes.
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Affiliation(s)
- William R Dunn
- Pharmacology Research Group, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
| | - Stephen P H Alexander
- Pharmacology Research Group, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Vera Ralevic
- Pharmacology Research Group, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Richard E Roberts
- Pharmacology Research Group, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom
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d’Emmanuele di Villa Bianca R, Mitidieri E, Esposito D, Donnarumm E, Russo A, Fusco F, Ianaro A, Mirone V, Cirino G, Russo G, Sorrentino R. Human Cystathionine-β-Synthase Phosphorylation on Serine227 Modulates Hydrogen Sulfide Production in Human Urothelium. PLoS One 2015; 10:e0136859. [PMID: 26368121 PMCID: PMC4569281 DOI: 10.1371/journal.pone.0136859] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/10/2015] [Indexed: 12/16/2022] Open
Abstract
Urothelium, the epithelial lining the inner surface of human bladder, plays a key role in bladder physiology and pathology. It responds to chemical, mechanical and thermal stimuli by releasing several factors and mediators. Recently it has been shown that hydrogen sulfide contributes to human bladder homeostasis. Hydrogen sulfide is mainly produced in human bladder by the action of cystathionine-β-synthase. Here, we demonstrate that human cystathionine-β-synthase activity is regulated in a cGMP/PKG-dependent manner through phosphorylation at serine 227. Incubation of human urothelium or T24 cell line with 8-Bromo-cyclic-guanosine monophosphate (8-Br-cGMP) but not dibutyryl-cyclic-adenosine monophosphate (d-cAMP) causes an increase in hydrogen sulfide production. This result is congruous with the finding that PKG is robustly expressed but PKA only weakly present in human urothelium as well as in T24 cells. The cGMP/PKG-dependent phosphorylation elicited by 8-Br-cGMP is selectively reverted by KT5823, a specific PKG inhibitor. Moreover, the silencing of cystathionine-β-synthase in T24 cells leads to a marked decrease in hydrogen sulfide production either in basal condition or following 8-Br-cGMP challenge. In order to identify the phosphorylation site, recombinant mutant proteins of cystathionine-β-synthase in which Ser32, Ser227 or Ser525 was mutated in Ala were generated. The Ser227Ala mutant cystathionine-β-synthase shows a notable reduction in basal biosynthesis of hydrogen sulfide becoming unresponsive to the 8-Br-cGMP challenge. A specific antibody that recognizes the phosphorylated form of cystathionine-β-synthase has been produced and validated by using T24 cells and human urothelium. In conclusion, human cystathionine-β-synthase can be phosphorylated in a PKG-dependent manner at Ser227 leading to an increased catalytic activity.
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Affiliation(s)
- Roberta d’Emmanuele di Villa Bianca
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, Italy
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, Italy
| | - Emma Mitidieri
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, Italy
| | - Davide Esposito
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, Naples, Italy
| | - Erminia Donnarumm
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, Italy
| | - Annapina Russo
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, Italy
| | - Ferdinando Fusco
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, Italy
- Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples, Federico II, Naples, Italy
| | - Angela Ianaro
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, Italy
| | - Vincenzo Mirone
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, Italy
- Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples, Federico II, Naples, Italy
| | - Giuseppe Cirino
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, Italy
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, Italy
- * E-mail:
| | - Giulia Russo
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, Italy
| | - Raffaella Sorrentino
- Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, Italy
- Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, Italy
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Wang R, Szabo C, Ichinose F, Ahmed A, Whiteman M, Papapetropoulos A. The role of H2S bioavailability in endothelial dysfunction. Trends Pharmacol Sci 2015; 36:568-78. [PMID: 26071118 DOI: 10.1016/j.tips.2015.05.007] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 05/16/2015] [Accepted: 05/18/2015] [Indexed: 11/25/2022]
Abstract
Endothelial dysfunction (EDF) reflects pathophysiological changes in the phenotype and functions of endothelial cells that result from and/or contribute to a plethora of cardiovascular diseases. We review the role of hydrogen sulfide (H2S) in the pathogenesis of EDF, one of the fastest advancing research topics. Conventionally treated as an environment pollutant, H2S is also produced in endothelial cells and participates in the fine regulation of endothelial integrity and functions. Disturbed H2S bioavailability has been suggested to be a novel indicator of EDF progress and prognosis. EDF manifests in different forms in multiple pathologies, but therapeutics aimed at remedying altered H2S bioavailability may benefit all.
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Affiliation(s)
- Rui Wang
- Department of Biology, Laurentian University, 935 Ramsey Lake Road, Sudbury, ON P3E 2C6, Canada.
| | - Csaba Szabo
- Department of Anesthesiology, The University of Texas Medical Branch at Galveston, 601 Harborside Drive, Galveston, TX 77555, USA
| | - Fumito Ichinose
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Asif Ahmed
- Aston Medical Research Institute, Aston Medical School, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Matthew Whiteman
- University of Exeter Medical School, St. Luke's Campus, Magdalen Road, Exeter EX1 2LU, UK
| | - Andreas Papapetropoulos
- Faculty of Pharmacy, University of Athens, Zografou Campus, Athens, 15771, Greece; George P. Livanos and Marianthi Simou Laboratories, First Department of Pulmonary and Critical Care Medicine, Evangelismos Hospital, Faculty of Medicine, University of Athens, Athens, 10675, Greece
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