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Taube N, Steiner M, Ebenebe-Kasonde OV, Kabir R, Garbus-Grant H, Alam El Din SM, Illingworth E, Wang N, Lin BL, Kohr MJ. Gestational arsenite exposure alters maternal postpartum heart size and induces Ca 2+-handling dysregulation in cardiomyocytes. Am J Physiol Heart Circ Physiol 2025; 328:H460-H471. [PMID: 39888327 DOI: 10.1152/ajpheart.00266.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/23/2024] [Accepted: 01/13/2025] [Indexed: 02/01/2025]
Abstract
Cardiovascular disease is the leading cause of mortality in the United States. Studies suggest a role for environmental exposures in the etiology of cardiovascular disease, including exposure to arsenic through drinking water. Arsenic exposure during pregnancy has been shown to have effects on offspring, but few studies have examined impacts on maternal cardiovascular health. Although our prior work documented the detrimental effect of arsenic on the maternal heart during pregnancy, our current study examines the effect of gestational arsenic exposure on the maternal heart postpartum. Timed-pregnant wild-type (C57BL/6J) mice were exposed to 0, 100, or 1,000 µg/L sodium arsenite (NaAsO2) via drinking water from embryonic day 2.5 until parturition. Postpartum heart structure and function was assessed via transthoracic echocardiography and gravimetric measurement. Hypertrophic markers were probed via qRT-PCR and Western blot. Isolated cardiomyocyte Ca2+-handling and contraction were also assessed, along with the expression of with Ca2+-handling and contractile proteins. Interestingly, we found that exposure to either 100 or 1,000 µg/L sodium arsenite increased postpartum heart size at postpartum day 12 vs. nonexposed postpartum controls. At the cellular level, we found altered cardiomyocyte Ca2+-handling and contraction, along with expression changes of key contractile proteins, including α-actin and cardiac myosin binding protein C (cMyBP-c). Together, these findings suggest that gestational arsenic exposure impacts the postpartum maternal heart, possibly inducing long-term cardiovascular changes. Furthermore, these findings highlight the importance of reducing arsenic exposure during pregnancy, and the need for more research on the impact of arsenic on maternal heart health and adverse pregnancy events.NEW & NOTEWORTHY Gestational exposure to sodium arsenite at environmentally relevant doses (100 and 1,000 µg/L) increases postpartum heart size, and induces dysregulated Ca2+ homeostasis and impaired shortening in isolated cardiomyocytes. This is the first study to demonstrate that gestational arsenic exposure impacts postpartum heart structure and function beyond the exposure period.
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Affiliation(s)
- Nicole Taube
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Morgan Steiner
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Obialunanma V Ebenebe-Kasonde
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Raihan Kabir
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Haley Garbus-Grant
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Sarah-Marie Alam El Din
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Emily Illingworth
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
| | - Nadan Wang
- Cardiology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Brian L Lin
- Cardiology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
- Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Mark J Kohr
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
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Meneses-Valdés R, Gallero S, Henríquez-Olguín C, Jensen TE. Exploring NADPH oxidases 2 and 4 in cardiac and skeletal muscle adaptations - A cross-tissue comparison. Free Radic Biol Med 2024; 223:296-305. [PMID: 39069268 DOI: 10.1016/j.freeradbiomed.2024.07.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 07/30/2024]
Abstract
Striated muscle cells, encompassing cardiac myocytes and skeletal muscle fibers, are fundamental to athletic performance, facilitating blood circulation and coordinated movement through contraction. Despite their distinct functional roles, these muscle types exhibit similarities in cytoarchitecture, protein expression, and excitation-contraction coupling. Both muscle types also undergo molecular remodeling in energy metabolism and cell size in response to acute and repeated exercise stimuli to enhance exercise performance. Reactive oxygen species (ROS) produced by NADPH oxidase (NOX) isoforms 2 and 4 have emerged as signaling molecules that regulate exercise adaptations. This review systematically compares NOX2 and NOX4 expression, regulation, and roles in cardiac and skeletal muscle responses across exercise modalities. We highlight the many gaps in our knowledge and opportunities to let future skeletal muscle research into NOX-dependent mechanisms be inspired by cardiac muscle studies and vice versa. Understanding these processes could enhance the development of exercise routines to optimize human performance and health strategies that capitalize on the advantages of physical activity.
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Affiliation(s)
- Roberto Meneses-Valdés
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Universitetsparken 13, Copenhagen, 2100, Denmark
| | - Samantha Gallero
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Universitetsparken 13, Copenhagen, 2100, Denmark; Advanced Center for Chronic Diseases (ACCDiS) and Department of Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Carlos Henríquez-Olguín
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Universitetsparken 13, Copenhagen, 2100, Denmark; Center of Exercise Physiology and Metabolism, Department of Kinesiology, Faculty of Medicine, Universidad Finis Terrae, Santiago, Chile.
| | - Thomas E Jensen
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Universitetsparken 13, Copenhagen, 2100, Denmark.
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Taube N, Steiner M, Ebenebe-Kasonde OV, Kabir R, Garbus-Grant H, Alam El Din SM, Illingworth E, Wang N, Lin BL, Kohr MJ. Gestational arsenite exposure alters maternal postpartum heart size and induces Ca 2+ handling dysregulation in cardiomyocytes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.25.615085. [PMID: 39386735 PMCID: PMC11463392 DOI: 10.1101/2024.09.25.615085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Cardiovascular disease is the leading cause of mortality in the US. Studies suggest a role for environmental exposures in the etiology of cardiovascular disease, including exposure to arsenic through drinking water. Arsenic exposure during pregnancy has been shown to have effects on offspring, but few studies have examined impacts on maternal cardiovascular health. While our prior work documented the detrimental effect of arsenic on the maternal heart during pregnancy, our current study examines the effect of gestational arsenic exposure on the maternal heart postpartum. Timed-pregnant wild-type (C57BL/6J) mice were exposed to 0, 100 or 1000 µg/L sodium arsenite (NaAsO2) via drinking water from embryonic day 2.5 (E2.5) until parturition. Postpartum heart structure and function was assessed via transthoracic echocardiography and gravimetric measurement. Hypertrophic markers were probed via qRT-PCR and western blot. Isolated cardiomyocyte Ca 2+ -handling and contraction were also assessed, and expression of proteins associated with Ca 2+ handling and contraction. Interestingly, we found that exposure to either 100 or 1000 µg/L sodium arsenite increased postpartum heart size at P12 vs. non-exposed postpartum controls. At the cellular level, we found altered cardiomyocyte Ca 2+ -handling and contraction. We also found altered expression of key contractile proteins, including α-Actin and cardiac myosin binding protein C (cMyBP-c). Together, these findings suggest that gestational arsenic exposure impacts the postpartum maternal heart, possibly inducing long-term cardiovascular changes. Furthermore, these findings highlight the importance of reducing arsenic exposure during pregnancy, and the need for more research on the impact of arsenic and other environmental exposures on maternal heart health and adverse pregnancy events. New & Noteworthy Gestational exposure to sodium arsenite at environmentally relevant doses (100 and 1000 µg/L) increases postpartum heart size, and induces dysregulated Ca 2+ homeostasis and impaired shortening in isolated cardiomyocytes. This is the first study to demonstrate that gestational arsenic exposure impacts postpartum heart structure and function beyond the exposure period.
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Elias-Llumbet A, Sharmin R, Berg-Sorensen K, Schirhagl R, Mzyk A. The Interplay between Mechanoregulation and ROS in Heart Physiology, Disease, and Regeneration. Adv Healthc Mater 2024; 13:e2400952. [PMID: 38962858 DOI: 10.1002/adhm.202400952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/16/2024] [Indexed: 07/05/2024]
Abstract
Cardiovascular diseases are currently the most common cause of death in developed countries. Due to lifestyle and environmental factors, this problem is only expected to increase in the future. Reactive oxygen species (ROS) are a key player in the onset of cardiovascular diseases but also have important functions in healthy cardiac tissue. Here, the interplay between ROS generation and cardiac mechanical forces is shown, and the state of the art and a perspective on future directions are discussed. To this end, an overview of what is currently known regarding ROS and mechanosignaling at a subcellular level is first given. There the role of ROS in mechanosignaling as well as the interplay between both factors in specific organelles is emphasized. The consequences at a larger scale across the population of heart cells are then discussed. Subsequently, the roles of ROS in embryogenesis, pathogenesis, and aging are further discussed, exemplifying some aspects of mechanoregulation. Finally, different models that are currently in use are discussed to study the topics above.
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Affiliation(s)
- Arturo Elias-Llumbet
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen, 9713AW, The Netherlands
- Laboratory of Genomic of Germ Cells, Biomedical Sciences Institute, Faculty of Medicine, University of Chile, Independencia, Santiago, 1027, Chile
| | - Rokshana Sharmin
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen, 9713AW, The Netherlands
| | | | - Romana Schirhagl
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen, 9713AW, The Netherlands
| | - Aldona Mzyk
- DTU Health Tech, Ørsteds Plads Bldg 345C, Kongens Lyngby, 2800, Denmark
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Feng C, Song J, Deng L, Zhang J, Lian X, Zhen Z, Liu J. Ginsenoside Rb1 reduces oxidative/carbonyl stress damage and dysfunction of RyR2 in the heart of streptozotocin-induced diabetic rats. BMC Cardiovasc Disord 2024; 24:333. [PMID: 38961333 PMCID: PMC11221176 DOI: 10.1186/s12872-024-04005-8] [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: 04/05/2024] [Accepted: 06/23/2024] [Indexed: 07/05/2024] Open
Abstract
BACKGROUND Oxidative stress may contribute to cardiac ryanodine receptor (RyR2) dysfunction in diabetic cardiomyopathy. Ginsenoside Rb1 (Rb1) is a major pharmacologically active component of ginseng to treat cardiovascular diseases. Whether Rb1 treat diabetes injured heart remains unknown. This study was to investigate the effect of Rb1 on diabetes injured cardiac muscle tissue and to further investigate its possible molecular pharmacology mechanisms. METHODS Male Sprague-Dawley rats were injected streptozotocin solution for 2 weeks, followed 6 weeks Rb1 or insulin treatment. The activity of SOD, CAT, Gpx, and the levels of MDA was measured; histological and ultrastructure analyses, RyR2 activity and phosphorylated RyR2(Ser2808) protein expression analyses; and Tunel assay were performed. RESULTS There was decreased activity of SOD, CAT, Gpx and increased levels of MDA in the diabetic group from control. Rb1 treatment increased activity of SOD, CAT, Gpx and decreased the levels of MDA as compared with diabetic rats. Neutralizing the RyR2 activity significantly decreased in diabetes from control, and increased in Rb1 treatment group from diabetic group. The expression of phosphorylation of RyR2 Ser2808 was increased in diabetic rats from control, and were attenuated with insulin and Rb1 treatment. Diabetes increased the apoptosis rate, and Rb1 treatment decreased the apoptosis rate. Rb1 and insulin ameliorated myocardial injury in diabetic rats. CONCLUSIONS These data indicate that Rb1 could be useful for mitigating oxidative damage, reduced phosphorylation of RyR2 Ser2808 and decreased the apoptosis rate of cardiomyocytes in diabetic cardiomyopathy.
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Affiliation(s)
- Chunpeng Feng
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, No 5. Beixiange Street, Beijing, 100053, China
| | - Jianping Song
- International Campus, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Haining, China
| | - Lan Deng
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, No 5. Beixiange Street, Beijing, 100053, China
| | - Jinfeng Zhang
- Jingmen Hospital of Traditional Chinese Medicine, Jingmen, China
| | - Xinyi Lian
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, No 5. Beixiange Street, Beijing, 100053, China
| | - Zhong Zhen
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, No 5. Beixiange Street, Beijing, 100053, China
| | - Jinfeng Liu
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, No 5. Beixiange Street, Beijing, 100053, China.
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Gómez-Viquez NL, Balderas-Villalobos J, Bello-Sánchez MD, Mayorga-Luna M, Mailloux-Salinas P, García-Castañeda M, Ríos-Pérez EB, Mártinez-Ávila MA, Camacho-Castillo LDC, Bravo G, Ávila G, Altamirano J, Carvajal K. Oxidative stress in early metabolic syndrome impairs cardiac RyR2 and SERCA2a activity and modifies the interplay of these proteins during Ca 2+ waves. Arch Physiol Biochem 2023; 129:1058-1070. [PMID: 33689540 DOI: 10.1080/13813455.2021.1895224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 02/19/2021] [Indexed: 10/21/2022]
Abstract
We investigated how oxidative stress (OS) alters Ca2+ handling in ventricular myocytes in early metabolic syndrome (MetS) in sucrose-fed rats. The effects of N-acetyl cysteine (NAC) or dl-Dithiothreitol (DTT) on systolic Ca2+ transients (SCaTs), diastolic Ca2+ sparks (CaS) and Ca2+ waves (CaW), recorded by confocal techniques, and L-type Ca2+ current (ICa), assessed by whole-cell patch clamp, were evaluated in MetS and Control cells. MetS myocytes exhibited decreased SCaTs and CaS frequency but unaffected CaW propagation. In Control cells, NAC/DTT reduced RyR2/SERCA2a activity blunting SCaTs, CaS frequency and CaW propagation, suggesting that basal ROS optimised Ca2+ signalling by maintaining RyR2/SERCA2a function and that these proteins facilitate CaW propagation. Conversely, NAC/DTT in MetS recovered RyR2/SERCA2a function, improving SCaTs and CaS frequency, but unexpectedly decreasing CaW propagation. We hypothesised that OS decreases RyR2/SERCA2a activity at early MetS, and while decreased SERCA2a favours CaW propagation, diminished RyR2 restrains it.
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Affiliation(s)
- Norma Leticia Gómez-Viquez
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, México
| | - Jaime Balderas-Villalobos
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, México
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Ciudad de México, México
| | - Ma Dolores Bello-Sánchez
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, México
| | - Maritza Mayorga-Luna
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, México
| | - Patrick Mailloux-Salinas
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, México
| | - Maricela García-Castañeda
- Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, México
| | - Erick Benjamín Ríos-Pérez
- Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, México
| | | | | | - Guadalupe Bravo
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, México
| | - Guillermo Ávila
- Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Ciudad de México, México
| | - Julio Altamirano
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, México
| | - Karla Carvajal
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Ciudad de México, México
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Nikolaienko R, Bovo E, Kahn D, Gracia R, Jamrozik T, Zima AV. Cysteines 1078 and 2991 cross-linking plays a critical role in redox regulation of cardiac ryanodine receptor (RyR). Nat Commun 2023; 14:4498. [PMID: 37495581 PMCID: PMC10372021 DOI: 10.1038/s41467-023-40268-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 07/19/2023] [Indexed: 07/28/2023] Open
Abstract
The most common cardiac pathologies, such as myocardial infarction and heart failure, are associated with oxidative stress. Oxidation of the cardiac ryanodine receptor (RyR2) Ca2+ channel causes spontaneous oscillations of intracellular Ca2+, resulting in contractile dysfunction and arrhythmias. RyR2 oxidation promotes the formation of disulfide bonds between two cysteines on neighboring RyR2 subunits, known as intersubunit cross-linking. However, the large number of cysteines in RyR2 has been a major hurdle in identifying the specific cysteines involved in this pathology-linked post-translational modification of the channel. Through mutagenesis of human RyR2 and in-cell Ca2+ imaging, we identify that only two cysteines (out of 89) in each RyR2 subunit are responsible for half of the channel's functional response to oxidative stress. Our results identify cysteines 1078 and 2991 as a redox-sensitive pair that forms an intersubunit disulfide bond between neighboring RyR2 subunits during oxidative stress, resulting in a pathological "leaky" RyR2 Ca2+ channel.
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Affiliation(s)
- Roman Nikolaienko
- Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Elisa Bovo
- Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Daniel Kahn
- Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Ryan Gracia
- Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Thomas Jamrozik
- Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Aleksey V Zima
- Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, 60153, USA.
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Zhu X, Kong X, Zang L, Sun N, Yu Q, Han L. Reactive oxygen species-mediated oxidative stress accelerates glycolysis via activation of the CaMKKβ/AMPK pathway in the yak longissimus dorsi postmortem. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2023; 103:514-523. [PMID: 36468614 DOI: 10.1002/jsfa.12161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 07/11/2022] [Accepted: 08/02/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Adenosine monophosphate-activated protein kinase (AMPK) is instrumental in the initiation of early postmortem glycolysis and the advent of pale, soft, and exudative (PSE) meat when cellular energy is altered. However, conflicting studies show that AMPK activation without corresponding energy level changes in PSE meat challenges this long-held notion. Here, we examined the effects of reactive oxygen species (ROS)-mediated oxidative stress on AMPK activation in the context of glycolysis, protein solubility, and water-holding capacity (WHC) in the postmortem yak longissimus dorsi (LD) muscle. Further, we explored the mechanisms underlying these effects. RESULTS Hydrogen peroxide (H2 O2 ) significantly augmented the degree of oxidative stress, increasing the production of ROS and malondialdehyde excessive production and reducing the activity of the anti-oxidants superoxide dismutase and glutathione peroxidase. In turn, oxidative stress dramatically promoted AMPK activation and glycolysis by increasing glycogen depletion and promoting hexokinase and phosphofructokinase activity. Subsequently, lactic acid accumulation increased, leading to a rapid decline in pH, which aggravated protein solubility degree and centrifugal loss in the early postmortem yak LD muscle. Importantly, these changes caused by oxidative stress were eliminated by the AMPK inhibitor. Mechanistically, oxidative stress elevated calcium ion (Ca2+ ) levels, which mobilized calcium/calmodulin-dependent protein kinase β (CaMKKβ) and AMPK. Rescue experiments confirmed that the increases were attenuated using Ca2+ and CaMKKβ chelators, respectively. CONCLUSION These results indicated that oxidative stress caused by ROS hastened early-stage postmortem glycolysis and reduced the WHC of yak meat. These effects were likely mediated by the alternative and energy-independent CaMKKβ/AMPK signaling pathway. © 2022 Society of Chemical Industry.
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Affiliation(s)
- Xijin Zhu
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, 730070, P. R. China
| | - Xiangying Kong
- Animal Husbandry and Veterinary Institute of Haibei Prefecture, Haibei, 812200, P. R. China
| | - Lei Zang
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, 730070, P. R. China
| | - Nan Sun
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, 730070, P. R. China
| | - Qunli Yu
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, 730070, P. R. China
| | - Ling Han
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, 730070, P. R. China
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Angelovski M, Hadzi-Petrushev N, Mitrokhin V, Kamkin A, Mladenov M. Myocardial infarction and oxidative damage in animal models: objective and expectations from the application of cysteine derivatives. Toxicol Mech Methods 2023; 33:1-17. [PMID: 35450505 DOI: 10.1080/15376516.2022.2069530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Reactive oxygen species (ROS) and associated oxidative stress are the main contributors to pathophysiological changes following myocardial infarction (MI), which is the principal cause of death from cardiovascular disease. The glutathione (GSH)/glutathione peroxidase (GPx) system appears to be the main and most active cardiac antioxidant mechanism. Hence, enhancement of the myocardial GSH system might have protective effects in the setting of MI. It follows that by increasing antioxidant capacity, the heart will be able to reduce the damage associated with MI and even prevent/weaken the occurrence of oxidative stress, which is highly ranked among the factors responsible for the occurrence of acute MI. For these reasons, the primary goal of future investigations should be to address the effects of different antioxidative compounds and especially cysteine derivatives like N-acetyl cysteine (NAC) and L-2-oxothiazolidine-4-carboxylic acid (OTC) as precursors responsible for the enhancement of the GSH-related antioxidant system's capacity. It is assumed that this will lay down the basis for elucidation of the mechanisms throughout which applicable doses of OTC will manifest a potentially positive impact in the reduction of adverse effects of acute MI. The inclusion of OTC in the models for prediction of the distribution of oxygen in infarcted animal hearts can help to upgrade existing computational models. Such a model would be based on computational geometries of the heart, but the inclusion of biochemical redox features in addition to angiogenic therapy, despite improvement of the post-infarcted oxygenated outcome could enhance the accuracy of the predictive values of oxygenation.
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Affiliation(s)
- Marija Angelovski
- Institute of Biology, Faculty of Natural Science and Mathematics, Ss Cyril and Methodius University, Skopje, North Macedonia
| | - Nikola Hadzi-Petrushev
- Institute of Biology, Faculty of Natural Science and Mathematics, Ss Cyril and Methodius University, Skopje, North Macedonia
| | - Vadim Mitrokhin
- Department of Fundamental and Applied Physiology, Russian National Research Medical University, Moscow, Russia
| | - Andre Kamkin
- Department of Fundamental and Applied Physiology, Russian National Research Medical University, Moscow, Russia
| | - Mitko Mladenov
- Institute of Biology, Faculty of Natural Science and Mathematics, Ss Cyril and Methodius University, Skopje, North Macedonia.,Department of Fundamental and Applied Physiology, Russian National Research Medical University, Moscow, Russia
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Chen H, Carty RK, Bautista AC, Hayakawa KA, Lein PJ. Triiodothyronine or Antioxidants Block the Inhibitory Effects of BDE-47 and BDE-49 on Axonal Growth in Rat Hippocampal Neuron-Glia Co-Cultures. TOXICS 2022; 10:92. [PMID: 35202279 PMCID: PMC8879960 DOI: 10.3390/toxics10020092] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/02/2022] [Accepted: 02/02/2022] [Indexed: 12/31/2022]
Abstract
We previously demonstrated that polybrominated diphenyl ethers (PBDEs) inhibit the growth of axons in primary rat hippocampal neurons. Here, we test the hypothesis that PBDE effects on axonal morphogenesis are mediated by thyroid hormone and/or reactive oxygen species (ROS)-dependent mechanisms. Axonal growth and ROS were quantified in primary neuronal-glial co-cultures dissociated from neonatal rat hippocampi exposed to nM concentrations of BDE-47 or BDE-49 in the absence or presence of triiodothyronine (T3; 3-30 nM), N-acetyl-cysteine (NAC; 100 µM), or α-tocopherol (100 µM). Co-exposure to T3 or either antioxidant prevented inhibition of axonal growth in hippocampal cultures exposed to BDE-47 or BDE-49. T3 supplementation in cultures not exposed to PBDEs did not alter axonal growth. T3 did, however, prevent PBDE-induced ROS generation and alterations in mitochondrial metabolism. Collectively, our data indicate that PBDEs inhibit axonal growth via ROS-dependent mechanisms, and that T3 protects axonal growth by inhibiting PBDE-induced ROS. These observations suggest that co-exposure to endocrine disruptors that decrease TH signaling in the brain may increase vulnerability to the adverse effects of developmental PBDE exposure on axonal morphogenesis.
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Affiliation(s)
| | | | | | | | - Pamela J. Lein
- Department of Molecular Biosciences, University of California, Davis, CA 95616, USA; (H.C.); (R.K.C.); (A.C.B.); (K.A.H.)
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Dhalla NS, Elimban V, Bartekova M, Adameova A. Involvement of Oxidative Stress in the Development of Subcellular Defects and Heart Disease. Biomedicines 2022; 10:biomedicines10020393. [PMID: 35203602 PMCID: PMC8962363 DOI: 10.3390/biomedicines10020393] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 02/01/2023] Open
Abstract
It is now well known that oxidative stress promotes lipid peroxidation, protein oxidation, activation of proteases, fragmentation of DNA and alteration in gene expression for producing myocardial cell damage, whereas its actions for the induction of fibrosis, necrosis and apoptosis are considered to result in the loss of cardiomyocytes in different types of heart disease. The present article is focused on the discussion concerning the generation and implications of oxidative stress from various sources such as defective mitochondrial electron transport and enzymatic reactions mainly due to the activation of NADPH oxidase, nitric oxide synthase and monoamine oxidase in diseased myocardium. Oxidative stress has been reported to promote excessive entry of Ca2+ due to increased permeability of the sarcolemmal membrane as well as depressions of Na+-K+ ATPase and Na+-Ca2+ exchange systems, which are considered to increase the intracellular of Ca2+. In addition, marked changes in the ryanodine receptors and Ca2+-pump ATPase have been shown to cause Ca2+-release and depress Ca2+ accumulation in the sarcoplasmic reticulum as a consequence of oxidative stress. Such alterations in sarcolemma and sarcoplasmic reticulum are considered to cause Ca2+-handling abnormalities, which are associated with mitochondrial Ca2+-overload and loss of myofibrillar Ca2+-sensitivity due to oxidative stress. Information regarding the direct effects of different oxyradicals and oxidants on subcellular organelles has also been outlined to show the mechanisms by which oxidative stress may induce Ca2+-handling abnormalities. These observations support the view that oxidative stress plays an important role in the genesis of subcellular defects and cardiac dysfunction in heart disease.
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Affiliation(s)
- Naranjan S. Dhalla
- St. Boniface Hospital Albrechtsen Research Centre, Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada;
- Correspondence: ; Tel.: +1-204-235-3417; Fax: +1-204-237-0347
| | - Vijayan Elimban
- St. Boniface Hospital Albrechtsen Research Centre, Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada;
| | - Monika Bartekova
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, Dubravska cesta 9, 84104 Bratislava, Slovakia; (M.B.); (A.A.)
| | - Adriana Adameova
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, Dubravska cesta 9, 84104 Bratislava, Slovakia; (M.B.); (A.A.)
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Odbojarov 10, 83232 Bratislava, Slovakia
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12
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The function and regulation of calsequestrin-2: implications in calcium-mediated arrhythmias. Biophys Rev 2022; 14:329-352. [PMID: 35340602 PMCID: PMC8921388 DOI: 10.1007/s12551-021-00914-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/14/2021] [Indexed: 01/09/2023] Open
Abstract
Cardiac arrhythmias are life-threatening events in which the heart develops an irregular rhythm. Mishandling of Ca2+ within the myocytes of the heart has been widely demonstrated to be an underlying mechanism of arrhythmogenesis. This includes altered function of the ryanodine receptor (RyR2)-the primary Ca2+ release channel located to the sarcoplasmic reticulum (SR). The spontaneous leak of SR Ca2+ via RyR2 is a well-established contributor in the development of arrhythmic contractions. This leak is associated with increased channel activity in response to changes in SR Ca2+ load. RyR2 activity can be regulated through several avenues, including interactions with numerous accessory proteins. One such protein is calsequestrin-2 (CSQ2), which is the primary Ca2+-buffering protein within the SR. The capacity of CSQ2 to buffer Ca2+ is tightly associated with the ability of the protein to polymerise in response to changing Ca2+ levels. CSQ2 can itself be regulated through phosphorylation and glycosylation modifications, which impact protein polymerisation and trafficking. Changes in CSQ2 modifications are implicated in cardiac pathologies, while mutations in CSQ2 have been identified in arrhythmic patients. Here, we review the role of CSQ2 in arrhythmogenesis including evidence for the indirect and direct regulation of RyR2 by CSQ2, and the consequences of a loss of functional CSQ2 in Ca2+ homeostasis and Ca2+-mediated arrhythmias. Supplementary Information The online version contains supplementary material available at 10.1007/s12551-021-00914-6.
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13
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Jaquenod De Giusti C, Palomeque J, Mattiazzi A. Ca 2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy. Pflugers Arch 2022; 474:33-61. [PMID: 34978597 PMCID: PMC8721633 DOI: 10.1007/s00424-021-02650-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 11/17/2021] [Accepted: 12/03/2021] [Indexed: 12/16/2022]
Abstract
Diabetic cardiomyopathy is defined as the myocardial dysfunction that suffers patients with diabetes mellitus (DM) in the absence of hypertension and structural heart diseases such as valvular or coronary artery dysfunctions. Since the impact of DM on cardiac function is rather silent and slow, early stages of diabetic cardiomyopathy, known as prediabetes, are poorly recognized, and, on many occasions, cardiac illness is diagnosed only after a severe degree of dysfunction was reached. Therefore, exploration and recognition of the initial pathophysiological mechanisms that lead to cardiac dysfunction in diabetic cardiomyopathy are of vital importance for an on-time diagnosis and treatment of the malady. Among the complex and intricate mechanisms involved in diabetic cardiomyopathy, Ca2+ mishandling and mitochondrial dysfunction have been described as pivotal early processes. In the present review, we will focus on these two processes and the molecular pathway that relates these two alterations to the earlier stages and the development of diabetic cardiomyopathy.
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Affiliation(s)
- Carolina Jaquenod De Giusti
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Médicas, UNLP, La Plata, Argentina
| | - Julieta Palomeque
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Médicas, UNLP, La Plata, Argentina
| | - Alicia Mattiazzi
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Médicas, UNLP, La Plata, Argentina.
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14
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Lipotoxicity: a driver of heart failure with preserved ejection fraction? Clin Sci (Lond) 2021; 135:2265-2283. [PMID: 34643676 PMCID: PMC8543140 DOI: 10.1042/cs20210127] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 12/17/2022]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a growing public health concern, with rising incidence alongside high morbidity and mortality. However, the pathophysiology of HFpEF is not yet fully understood. The association between HFpEF and the metabolic syndrome (MetS) suggests that dysregulated lipid metabolism could drive diastolic dysfunction and subsequent HFpEF. Herein we summarise recent advances regarding the pathogenesis of HFpEF in the context of MetS, with a focus on impaired lipid handling, myocardial lipid accumulation and subsequent lipotoxicity.
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15
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Chatterji A, Sengupta R. Stability of S-nitrosothiols and S-nitrosylated proteins: A struggle for cellular existence! J Cell Biochem 2021; 122:1579-1593. [PMID: 34472139 DOI: 10.1002/jcb.30139] [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: 06/17/2021] [Revised: 07/29/2021] [Accepted: 08/19/2021] [Indexed: 12/15/2022]
Abstract
Nitric oxide is a well-known gasotransmitter molecule that covalently docks to sulfhydryl groups of proteins resulting in S-nitrosylation of proteins and nonprotein thiols that serve a variety of cellular processes including cGMP signaling, vasodilatation, neurotransmission, ion-channel modulation, and cardiac signaling. S-nitrosylation is an indispensable modification like phosphorylation that directly regulates the functionality of numerous proteins. However, recently there has been a controversy over the stability of S-nitrosylated proteins (PSNOs) within the cell. It has been argued that PSNOs formed within the cell is a transient intermediate step to more stable disulfide formation and disulfides are the predominant end effector modifications in NO-mediated signaling. The present article accumulates state-of-the-art evidence from numerous research that strongly supports the very existence of PSNOs within the cell and attempts to put an end to the controversy. This review illustrates critical points including comparative bond dissociation energies of S-NO bond, the half-life of S-nitrosothiols and PSNOs, cellular concentrations of PSNOs, X ray crystallographic studies on PSNOs, and stability of PSNOs at physiological concentration of antioxidants. These logical evidence cumulatively support the endogenous stability and inevitable existence of PSNOs/RSNOs within the cell that directly regulate the functionality of proteins and provide valuable insight into understanding stable S-nitrosylation mediated cell signaling.
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Affiliation(s)
- Ajanta Chatterji
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Kolkata, India
| | - Rajib Sengupta
- Amity Institute of Biotechnology Kolkata, Amity University Kolkata, Kolkata, India
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16
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Wang L, Ginnan RG, Wang YX, Zheng YM. Interactive Roles of CaMKII/Ryanodine Receptor Signaling and Inflammation in Lung Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:305-317. [PMID: 33788199 DOI: 10.1007/978-3-030-63046-1_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional protein kinase and has been recently recognized to play a vital role in pathological events in the pulmonary system. CaMKII has diverse downstream targets that promote vascular disease, asthma, and cancer, so improved understanding of CaMKII signaling has the potential to lead to new therapies for lung diseases. Multiple studies have demonstrated that CaMKII is involved in redox modulation of ryanodine receptors (RyRs). CaMKII can be directly activated by reactive oxygen species (ROS) which then regulates RyR activity, which is essential for Ca2+-dependent processes in lung diseases. Furthermore, both CaMKII and RyRs participate in the inflammation process. However, their role in the pulmonary physiology in response to ROS is still an ambiguous one. Because CaMKII and RyRs are important in pulmonary biology, cell survival, cell cycle control, and inflammation, it is possible that the relationship between ROS and CaMKII/RyRs signal complex will be necessary for understanding and treating lung diseases. Here, we review roles of CaMKII/RyRs in lung diseases to understand with how CaMKII/RyRs may act as a transduction signal to connect prooxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of pulmonary disease.
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Affiliation(s)
- Lan Wang
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.,Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Roman G Ginnan
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Yong-Xiao Wang
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
| | - Yun-Min Zheng
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
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17
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Association of serum vitamin D status with development of type 2 diabetes: A retrospective cross-sectional study. CLINICAL NUTRITION OPEN SCIENCE 2021. [DOI: 10.1016/j.nutos.2020.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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18
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Dridi H, Kushnir A, Zalk R, Yuan Q, Melville Z, Marks AR. Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target. Nat Rev Cardiol 2020; 17:732-747. [PMID: 32555383 PMCID: PMC8362847 DOI: 10.1038/s41569-020-0394-8] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/06/2020] [Indexed: 12/14/2022]
Abstract
Ca2+ is a fundamental second messenger in all cell types and is required for numerous essential cellular functions, including cardiac and skeletal muscle contraction. The intracellular concentration of free Ca2+ ([Ca2+]) is regulated primarily by ion channels, pumps (ATPases), exchangers and Ca2+-binding proteins. Defective regulation of [Ca2+] is found in a diverse spectrum of pathological states that affect all the major organs. In the heart, abnormalities in the regulation of cytosolic and mitochondrial [Ca2+] occur in heart failure (HF) and atrial fibrillation (AF), two common forms of heart disease and leading contributors to morbidity and mortality. In this Review, we focus on the mechanisms that regulate ryanodine receptor 2 (RYR2), the major sarcoplasmic reticulum (SR) Ca2+-release channel in the heart, how RYR2 becomes dysfunctional in HF and AF, and its potential as a therapeutic target. Inherited RYR2 mutations and/or stress-induced phosphorylation and oxidation of the protein destabilize the closed state of the channel, resulting in a pathological diastolic Ca2+ leak from the SR that both triggers arrhythmias and impairs contractility. On the basis of our increased understanding of SR Ca2+ leak as a shared Ca2+-dependent pathological mechanism in HF and AF, a new class of drugs developed in our laboratory, known as rycals, which stabilize RYR2 channels and prevent Ca2+ leak from the SR, are undergoing investigation in clinical trials.
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Affiliation(s)
- Haikel Dridi
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Alexander Kushnir
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Ran Zalk
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Qi Yuan
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Zephan Melville
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Andrew R Marks
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
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19
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Nikolaienko R, Bovo E, Rebbeck RT, Kahn D, Thomas DD, Cornea RL, Zima AV. The functional significance of redox-mediated intersubunit cross-linking in regulation of human type 2 ryanodine receptor. Redox Biol 2020; 37:101729. [PMID: 32980662 PMCID: PMC7522892 DOI: 10.1016/j.redox.2020.101729] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/19/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
The type 2 ryanodine receptor (RyR2) plays a key role in the cardiac intracellular calcium (Ca2+) regulation. We have previously shown that oxidative stress activates RyR2 in rabbit cardiomyocytes by promoting the formation of disulfide bonds between neighboring RyR2 subunits. However, the functional significance of this redox modification for human RyR2 (hRyR2) remains largely unknown. Here, we studied the redox regulation of hRyR2 in HEK293 cells transiently expressing the ryr2 gene. Analysis of hRyR2 cross-linking and of the redox-GFP readout response to diamide oxidation revealed that hRyR2 cysteines involved in the intersubunit cross-linking are highly sensitive to oxidative stress. In parallel experiments, the effect of diamide on endoplasmic reticulum (ER) Ca2+ release was studied in cells co-transfected with hRyR2, ER Ca2+ pump (SERCA2a) and the ER-targeted Ca2+ sensor R-CEPIA1er. Expression of hRyR2 and SERCA2a produced “cardiac-like” Ca2+ waves due to spontaneous hRyR2 activation. Incubation with diamide caused a fast decline of the luminal ER Ca2+ (or ER Ca2+ load) followed by the cessation of Ca2+ waves. The maximal effect of diamide on ER Ca2+ load and Ca2+ waves positively correlates with the maximum level of hRyR2 cross-linking, indicating a functional significance of this redox modification. Furthermore, the level of hRyR2 cross-linking positively correlates with the degree of calmodulin (CaM) dissociation from the hRyR2 complex. In skeletal muscle RyR (RyR1), cysteine 3635 (C3635) is viewed as dominantly responsible for the redox regulation of the channel. Here, we showed that the corresponding cysteine 3602 (C3602) in hRyR2 does not participate in intersubunit cross-linking and plays a limited role in the hRyR2 regulation by CaM during oxidative stress. Collectively, these results suggest that redox-mediated intersubunit cross-linking is an important regulator of hRyR2 function under pathological conditions associated with oxidative stress.
Oxidative stress promotes cardiac ryanodine receptor (RyR2) intersubunit crosslinking. Human RyR2 crosslinking promotes Ca leak and calmodulin dissociation. RyR2 C3602 is not involved in crosslinking, slightly affects calmodulin binding. RyR2 crosslinking is an important pathology related RyR2 regulator.
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Affiliation(s)
- Roman Nikolaienko
- Department of Cell and Molecular Physiology, Loyola University Chicago, IL, USA
| | - Elisa Bovo
- Department of Cell and Molecular Physiology, Loyola University Chicago, IL, USA
| | - Robyn T Rebbeck
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Daniel Kahn
- Department of Cell and Molecular Physiology, Loyola University Chicago, IL, USA
| | - David D Thomas
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Razvan L Cornea
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Aleksey V Zima
- Department of Cell and Molecular Physiology, Loyola University Chicago, IL, USA.
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20
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Zhang DM, Lin YF. Functional modulation of sarcolemmal K ATP channels by atrial natriuretic peptide-elicited intracellular signaling in adult rabbit ventricular cardiomyocytes. Am J Physiol Cell Physiol 2020; 319:C194-C207. [PMID: 32432931 DOI: 10.1152/ajpcell.00409.2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
ATP-sensitive potassium (KATP) channels couple cell metabolic status to membrane excitability and are crucial for stress adaptation and cytoprotection in the heart. Atrial natriuretic peptide (ANP), a cardiac peptide important for cardiovascular homeostasis, also exhibits cytoprotective features including protection against myocardial ischemia-reperfusion injuries. However, how ANP modulates cardiac KATP channels is largely unknown. In the present study we sought to address this issue by investigating the role of ANP signaling in functional modulation of sarcolemmal KATP (sarcKATP) channels in ventricular myocytes freshly isolated from adult rabbit hearts. Single-channel recordings were performed in combination with pharmacological approaches in the cell-attached patch configuration. Bath application of ANP markedly potentiated sarcKATP channel activities induced by metabolic inhibition with sodium azide, whereas the KATP-stimulating effect of ANP was abrogated by selective inhibition of the natriuretic peptide receptor type A (NPR-A), cGMP-dependent protein kinase (PKG), reactive oxygen species (ROS), extracellular signal-regulated protein kinase (ERK)1/2, Ca2+/calmodulin-dependent protein kinase II (CaMKII), or the ryanodine receptor (RyR). Blockade of RyRs also nullified hydrogen peroxide (H2O2)-induced stimulation of sarcKATP channels in intact cells. Furthermore, single-channel kinetic analyses revealed that ANP enhanced the function of ventricular sarcKATP channels through destabilizing the long closures and facilitating the opening transitions, without affecting the single-channel conductance. In conclusion, here we report that ANP positively modulates the activity of ventricular sarcKATP channels via an intracellular signaling mechanism consisting of NPR-A, PKG, ROS, ERK1/2, CaMKII, and RyR2. This novel mechanism may regulate cardiac excitability and contribute to cytoprotection, in part, by opening myocardial KATP channels.
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Affiliation(s)
- Dai-Min Zhang
- Department of Physiology and Membrane Biology, University of California, Davis, California
| | - Yu-Fung Lin
- Department of Physiology and Membrane Biology, University of California, Davis, California.,Department of Anesthesiology and Pain Medicine, University of California, Davis, California
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21
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Molecular mechanisms by which iNOS uncoupling can induce cardiovascular dysfunction during sepsis: Role of posttranslational modifications (PTMs). Life Sci 2020; 255:117821. [PMID: 32445759 DOI: 10.1016/j.lfs.2020.117821] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/14/2020] [Accepted: 05/18/2020] [Indexed: 01/01/2023]
Abstract
Human sepsis is the result of a multifaceted pathological process causing marked dysregulation of cardiovascular responses. A more sophisticated understanding of the pathogenesis of sepsis is certainly prerequisite. Evidence from studies provide further insight into the role of inducible nitric oxide synthase (iNOS) isoform. Results on inhibition of iNOS in sepsis models remain inconclusive. Concern has been devoted to improving our knowledge and understanding of the role of iNOS. The aim of this review is to define the role of iNOS in redox homeostasis disturbance, the detailed mechanisms linking iNOS and posttranslational modifications (PTMs) to cardiovascular dysfunctions, and their future implications in sepsis settings. Many questions related to the iNOS and PTMs still remain open, and much more work is needed on this.
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22
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Muñoz P, Ardiles ÁO, Pérez-Espinosa B, Núñez-Espinosa C, Paula-Lima A, González-Billault C, Espinosa-Parrilla Y. Redox modifications in synaptic components as biomarkers of cognitive status, in brain aging and disease. Mech Ageing Dev 2020; 189:111250. [PMID: 32433996 DOI: 10.1016/j.mad.2020.111250] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/05/2020] [Accepted: 04/10/2020] [Indexed: 02/06/2023]
Abstract
Aging is a natural process that includes several changes that gradually make organisms degenerate and die. Harman's theory proposes that aging is a consequence of the progressive accumulation of oxidative modifications mediated by reactive oxygen/nitrogen species, which plays an essential role in the development and progression of many neurodegenerative diseases. This review will focus on how abnormal redox modifications induced by age impair the functionality of neuronal redox-sensitive proteins involved in axonal elongation and guidance, synaptic plasticity, and intercellular communication. We will discuss post-transcriptional regulation of gene expression by microRNAs as a mechanism that controls the neuronal redox state. Finally, we will discuss how some brain-permeant antioxidants from the diet have a beneficial effect on cognition. Taken together, the evidence revised here indicates that oxidative-driven modifications of specific proteins and changes in microRNA expression may be useful biomarkers for aging and neurodegenerative diseases. Also, some specific antioxidant therapies have undoubtedly beneficial neuroprotective effects when administered in the correct doses, in the ideal formulation combination, and during the appropriate therapeutic window. The use of some antioxidants is, therefore, still poorly explored for the treatment of neurodegenerative diseases such as Alzheimer's disease.
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Affiliation(s)
- Pablo Muñoz
- Department of Pathology and Physiology, Medical School, Faculty of Medicine, Universidad de Valparaíso, Valparaíso, Chile; Translational Neurology Center, Faculty of Medicine, Universidad de Valparaíso, Valparaíso, Chile; Biomedical Research Center, Universidad de Valparaíso, Valparaíso, Chile; Thematic Task Force on Healthy Aging, CUECH Research Network.
| | - Álvaro O Ardiles
- Department of Pathology and Physiology, Medical School, Faculty of Medicine, Universidad de Valparaíso, Valparaíso, Chile; Translational Neurology Center, Faculty of Medicine, Universidad de Valparaíso, Valparaíso, Chile; Thematic Task Force on Healthy Aging, CUECH Research Network; Interdisciplinary Center of Neuroscience of Valparaíso, Universidad de Valparaíso, Valparaíso, Chile; Interdisciplinary Center for Health Studies, Universidad de Valparaíso, Valparaíso, Chile
| | - Boris Pérez-Espinosa
- Thematic Task Force on Healthy Aging, CUECH Research Network; Laboratorio biología de la Reproduccion, Departamento Biomédico, Facultad Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile
| | - Cristian Núñez-Espinosa
- Thematic Task Force on Healthy Aging, CUECH Research Network; School of Medicine, Universidad de Magallanes, Punta Arenas, Chile
| | - Andrea Paula-Lima
- Thematic Task Force on Healthy Aging, CUECH Research Network; Institute for Research in Dental Sciences, Faculty of Dentistry; Universidad de Chile, Santiago, Chile; Biomedical Neuroscience Institute (BNI) and Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Christian González-Billault
- Thematic Task Force on Healthy Aging, CUECH Research Network; Laboratory of Cell and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile; FONDAP Geroscience Center for Brain Health and Metabolism, Santiago, Chile; Buck Institute for Research on Aging, Novato, CA, USA.
| | - Yolanda Espinosa-Parrilla
- Thematic Task Force on Healthy Aging, CUECH Research Network; School of Medicine, Universidad de Magallanes, Punta Arenas, Chile; Laboratory of Molecular Medicine - LMM, Center for Education, Healthcare and Investigation - CADI, University of Magallanes, Punta Arenas, Chile.
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23
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Rousset F, Nacher-Soler G, Coelho M, Ilmjarv S, Kokje VBC, Marteyn A, Cambet Y, Perny M, Roccio M, Jaquet V, Senn P, Krause KH. Redox activation of excitatory pathways in auditory neurons as mechanism of age-related hearing loss. Redox Biol 2020; 30:101434. [PMID: 32000019 PMCID: PMC7016250 DOI: 10.1016/j.redox.2020.101434] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/08/2020] [Accepted: 01/14/2020] [Indexed: 12/20/2022] Open
Abstract
Age-related hearing (ARHL) loss affects a large part of the human population with a major impact on our aging societies. Yet, underlying mechanisms are not understood, and no validated therapy or prevention exists. NADPH oxidases (NOX), are important sources of reactive oxygen species (ROS) in the cochlea and might therefore be involved in the pathogenesis of ARHL. Here we investigate ARHL in a mouse model. Wild type mice showed early loss of hearing and cochlear integrity, while animals deficient in the NOX subunit p22phox remained unaffected up to six months. Genes of the excitatory pathway were down-regulated in p22phox-deficient auditory neurons. Our results demonstrate that NOX activity leads to upregulation of genes of the excitatory pathway, to excitotoxic cochlear damage, and ultimately to ARHL. In the absence of functional NOXs, aging mice conserve hearing and cochlear morphology. Our study offers new insights into pathomechanisms and future therapeutic targets of ARHL.
Mice devoid of NADPH oxidase (NOX) activity are protected from age-related hearing loss. Cochlear NOX expression shows a similar pattern in mouse and human. NOX3, the predominant NOX isoform in the cochlea, is mostly expressed in auditory neurons. NOX-deficient auditory neurons show decreased transcription of glutamatergic pathway and are protected from excitotoxicity. NOX-mediated gene regulation within auditory neurons contributes to age-related hearing loss.
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Affiliation(s)
- Francis Rousset
- Hearing and Olfaction Research Laboratory, Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland.
| | - German Nacher-Soler
- Hearing and Olfaction Research Laboratory, Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland
| | - Marta Coelho
- Hearing and Olfaction Research Laboratory, Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland
| | - Sten Ilmjarv
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland
| | - Vivianne Beatrix Christina Kokje
- Hearing and Olfaction Research Laboratory, Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland
| | - Antoine Marteyn
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland
| | - Yves Cambet
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland; READS Unit, Faculty of Medicine, University of Geneva, Switzerland
| | - Michael Perny
- Department of Biomedical Research (DBMR), University of Bern, Switzerland; Department of Otorhinolaryngology, Inselspital Bern, Switzerland
| | - Marta Roccio
- Department of Biomedical Research (DBMR), University of Bern, Switzerland; Department of Otorhinolaryngology, Inselspital Bern, Switzerland
| | - Vincent Jaquet
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland; READS Unit, Faculty of Medicine, University of Geneva, Switzerland
| | - Pascal Senn
- Hearing and Olfaction Research Laboratory, Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland; Department of Clinical Neurosciences, Service of ORL & Head and Neck Surgery, University Hospital of Geneva, Switzerland
| | - Karl Heinz Krause
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland
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Lovering RC, Roncaglia P, Howe DG, Laulederkind SJF, Khodiyar VK, Berardini TZ, Tweedie S, Foulger RE, Osumi-Sutherland D, Campbell NH, Huntley RP, Talmud PJ, Blake JA, Breckenridge R, Riley PR, Lambiase PD, Elliott PM, Clapp L, Tinker A, Hill DP. Improving Interpretation of Cardiac Phenotypes and Enhancing Discovery With Expanded Knowledge in the Gene Ontology. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2019; 11:e001813. [PMID: 29440116 PMCID: PMC5821137 DOI: 10.1161/circgen.117.001813] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 01/11/2018] [Indexed: 12/17/2022]
Abstract
Supplemental Digital Content is available in the text. Background: A systems biology approach to cardiac physiology requires a comprehensive representation of how coordinated processes operate in the heart, as well as the ability to interpret relevant transcriptomic and proteomic experiments. The Gene Ontology (GO) Consortium provides structured, controlled vocabularies of biological terms that can be used to summarize and analyze functional knowledge for gene products. Methods and Results: In this study, we created a computational resource to facilitate genetic studies of cardiac physiology by integrating literature curation with attention to an improved and expanded ontological representation of heart processes in the Gene Ontology. As a result, the Gene Ontology now contains terms that comprehensively describe the roles of proteins in cardiac muscle cell action potential, electrical coupling, and the transmission of the electrical impulse from the sinoatrial node to the ventricles. Evaluating the effectiveness of this approach to inform data analysis demonstrated that Gene Ontology annotations, analyzed within an expanded ontological context of heart processes, can help to identify candidate genes associated with arrhythmic disease risk loci. Conclusions: We determined that a combination of curation and ontology development for heart-specific genes and processes supports the identification and downstream analysis of genes responsible for the spread of the cardiac action potential through the heart. Annotating these genes and processes in a structured format facilitates data analysis and supports effective retrieval of gene-centric information about cardiac defects.
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Affiliation(s)
- Ruth C Lovering
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.).
| | - Paola Roncaglia
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Douglas G Howe
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Stanley J F Laulederkind
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Varsha K Khodiyar
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Tanya Z Berardini
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Susan Tweedie
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Rebecca E Foulger
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - David Osumi-Sutherland
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Nancy H Campbell
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Rachael P Huntley
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Philippa J Talmud
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Judith A Blake
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Ross Breckenridge
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Paul R Riley
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Pier D Lambiase
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Perry M Elliott
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Lucie Clapp
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - Andrew Tinker
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
| | - David P Hill
- From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.)
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Poluektov YM, Petrushanko IY, Undrovinas NA, Lakunina VA, Khapchaev AY, Kapelko VI, Abramov AA, Lakomkin VL, Novikov MS, Shirinsky VP, Mitkevich VA, Makarov AA. Glutathione-related substances maintain cardiomyocyte contractile function in hypoxic conditions. Sci Rep 2019; 9:4872. [PMID: 30890744 PMCID: PMC6425009 DOI: 10.1038/s41598-019-41266-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 02/04/2019] [Indexed: 12/20/2022] Open
Abstract
Severe hypoxia leads to decline in cardiac contractility and induces arrhythmic events in part due to oxidative damage to cardiomyocyte proteins including ion transporters. This results in compromised handling of Ca2+ ions that trigger heart contractile machinery. Here, we demonstrate that thiol-containing compounds such as N-acetylcysteine (NAC), glutathione ethyl ester (et-GSH), oxidized tetraethylglutathione (tet-GSSG), oxidized glutathione (GSSG) and S-nitrosoglutathione (GSNO) are capable of reducing negative effects of hypoxia on isolated rat cardiomyocytes. Preincubation of cardiomyocytes with 0.1 mM GSNO, 0.5 mM et-GSH, GSSG, tet-GSSG or with 10 mM NAC allows cells 5-times longer tolerate the hypoxic conditions and elicit regular Ca2+ transients in response to electric pacing. The shape of Ca2+ transients generated in the presence of GSNO, et-GSH and NAC was similar to that observed in normoxic control cardiomyocytes. The leader compound, GSNO, accelerated by 34% the recovery of normal contractile function of isolated rat heart subjected to ischemia-reperfusion. GSNO increased glutathionylation of Na,K-ATPase alpha-2 subunit, the principal ion-transporter of cardiac myocyte sarcolemma, which prevents irreversible oxidation of Na,K-ATPase and regulates its function to support normal Ca2+ ion handling in hypoxic cardiomyocytes. Altogether, GSNO appears effective cardioprotector in hypoxic conditions worth further studies toward its cardiovascular application.
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Affiliation(s)
- Yuri M Poluektov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991, Moscow, Russia
- I.M. Sechenov First Moscow State Medical University, Ministry of Healthcare of the Russian Federation, Trubetskaya St. 8/2, 119991, Moscow, Russia
| | - Irina Yu Petrushanko
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991, Moscow, Russia
| | - Nidas A Undrovinas
- National Medical Research Center for Cardiology, Ministry of Healthcare of the Russian Federation, 3rd Cherepkovskaya St. 15a, Moscow, 121552, Russia
| | - Valentina A Lakunina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991, Moscow, Russia
| | - Asker Y Khapchaev
- National Medical Research Center for Cardiology, Ministry of Healthcare of the Russian Federation, 3rd Cherepkovskaya St. 15a, Moscow, 121552, Russia
| | - Valery I Kapelko
- National Medical Research Center for Cardiology, Ministry of Healthcare of the Russian Federation, 3rd Cherepkovskaya St. 15a, Moscow, 121552, Russia
| | - Alexander A Abramov
- National Medical Research Center for Cardiology, Ministry of Healthcare of the Russian Federation, 3rd Cherepkovskaya St. 15a, Moscow, 121552, Russia
| | - Vladimir L Lakomkin
- National Medical Research Center for Cardiology, Ministry of Healthcare of the Russian Federation, 3rd Cherepkovskaya St. 15a, Moscow, 121552, Russia
| | - Mikhail S Novikov
- Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, Pavshikh Bortsov Sq. 1, Volgograd, 400131, Russia
| | - Vladimir P Shirinsky
- National Medical Research Center for Cardiology, Ministry of Healthcare of the Russian Federation, 3rd Cherepkovskaya St. 15a, Moscow, 121552, Russia
| | - Vladimir A Mitkevich
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991, Moscow, Russia
| | - Alexander A Makarov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991, Moscow, Russia.
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Scirè A, Cianfruglia L, Minnelli C, Bartolini D, Torquato P, Principato G, Galli F, Armeni T. Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways. Biofactors 2019; 45:152-168. [PMID: 30561781 DOI: 10.1002/biof.1476] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/23/2018] [Accepted: 10/24/2018] [Indexed: 12/20/2022]
Abstract
Glutathione is considered the major non-protein low molecular weight modulator of redox processes and the most important thiol reducing agent of the cell. The biosynthesis of glutathione occurs in the cytosol from its constituent amino acids, but this tripeptide is also present in the most important cellular districts, such as mitochondria, nucleus, and endoplasmic reticulum, thus playing a central role in several metabolic pathways and cytoprotection mechanisms. Indeed, glutathione is involved in the modulation of various cellular processes and, not by chance, it is a ubiquitous determinant for redox signaling, xenobiotic detoxification, and regulation of cell cycle and death programs. The balance between its concentration and redox state is due to a complex series of interactions between biosynthesis, utilization, degradation, and transport. All these factors are of great importance to understand the significance of cellular redox balance and its relationship with physiological responses and pathological conditions. The purpose of this review is to give an overview on glutathione cellular compartmentalization. Information on its subcellular distribution provides a deeper understanding of glutathione-dependent processes and reflects the importance of compartmentalization in the regulation of specific cellular pathways. © 2018 BioFactors, 45(2):152-168, 2019.
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Affiliation(s)
- Andrea Scirè
- Department of Life and Environmental Sciences, Università Politecnica delle Marche, Ancona, Italy
| | - Laura Cianfruglia
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica delle Marche, Ancona, Italy
| | - Cristina Minnelli
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica delle Marche, Ancona, Italy
| | - Desirée Bartolini
- Clinical Biochemistry and Human Nutrition Labs, Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Pierangelo Torquato
- Clinical Biochemistry and Human Nutrition Labs, Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Giovanni Principato
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica delle Marche, Ancona, Italy
| | - Francesco Galli
- Clinical Biochemistry and Human Nutrition Labs, Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Tatiana Armeni
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica delle Marche, Ancona, Italy
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Nikolaienko R, Bovo E, Zima AV. Redox Dependent Modifications of Ryanodine Receptor: Basic Mechanisms and Implications in Heart Diseases. Front Physiol 2018; 9:1775. [PMID: 30574097 PMCID: PMC6291498 DOI: 10.3389/fphys.2018.01775] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 11/23/2018] [Indexed: 12/12/2022] Open
Abstract
Heart contraction vitally depends on tightly controlled intracellular Ca regulation. Because contraction is mainly driven by Ca released from the sarcoplasmic reticulum (SR), this organelle plays a particularly important role in Ca regulation. The type two ryanodine receptor (RyR2) is the major SR Ca release channel in ventricular myocytes. Several cardiac pathologies, including myocardial infarction and heart failure, are associated with increased RyR2 activity and diastolic SR Ca leak. It has been suggested that the increased RyR2 activity plays an important role in arrhythmias and contractile dysfunction. Several studies have linked increased SR Ca leak during myocardial infarction and heart failure to the activation of RyR2 in response to oxidative stress. This activation might include direct oxidation of RyR2 as well as indirect activation via phosphorylation or altered interactions with regulatory proteins. Out of ninety cysteine residues per RyR2 subunit, twenty one were reported to be in reduced state that could be potential targets for redox modifications that include S-nitrosylation, S-glutathionylation, and disulfide cross-linking. Despite its clinical significance, molecular mechanisms of RyR dysfunction during oxidative stress are not fully understood. Herein we review the most recent insights into redox-dependent modulation of RyR2 during oxidative stress and heart diseases.
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Affiliation(s)
- Roman Nikolaienko
- Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, United States
| | - Elisa Bovo
- Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, United States
| | - Aleksey V Zima
- Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, United States
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González-Montero J, Brito R, Gajardo AIJ, Rodrigo R. Myocardial reperfusion injury and oxidative stress: Therapeutic opportunities. World J Cardiol 2018; 10:74-86. [PMID: 30344955 PMCID: PMC6189069 DOI: 10.4330/wjc.v10.i9.74] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/27/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty (PCA) treatment, which quickly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxically, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species (ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury (MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies (mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weaknesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention, and its continuity may also have some responsibility for the lack of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine (a glutathione donor) and deferoxamine (an iron chelator) could improve the antioxidant cardioprotection by ascorbate, making it even more effective in preventing myocardial reperfusion damage associated with PCA following AMI.
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Affiliation(s)
- Jaime González-Montero
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
| | - Roberto Brito
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
- Internal Medicine Department, University of Chile, Clinical Hospital, Santiago 70058, Chile
| | - Abraham IJ Gajardo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
- Internal Medicine Department, University of Chile, Clinical Hospital, Santiago 70058, Chile
| | - Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70058, Chile
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Muñoz Y, Paula-Lima AC, Núñez MT. Reactive oxygen species released from astrocytes treated with amyloid beta oligomers elicit neuronal calcium signals that decrease phospho-Ser727-STAT3 nuclear content. Free Radic Biol Med 2018; 117:132-144. [PMID: 29309895 DOI: 10.1016/j.freeradbiomed.2018.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 12/19/2017] [Accepted: 01/04/2018] [Indexed: 02/06/2023]
Abstract
The transcription factor STAT3 has a crucial role in the development and maintenance of the nervous system. In this work, we treated astrocytes with oligomers of the amyloid beta peptide (AβOs), which display potent synaptotoxic activity, and studied the effects of mediators released by AβOs-treated astrocytes on the nuclear location of neuronal serine-727-phosphorylated STAT3 (pSerSTAT3). Treatment of mixed neuron-astrocyte cultures with 0.5µMAβOs induced in neurons a significant decrease of nuclear pSerSTAT3, but not of phosphotyrosine-705 STAT3, the other form of STAT3 phosphorylation. This decrease did not occur in astrocyte-poor neuronal cultures revealing a pivotal role for astrocytes in this response. To test if mediators released by astrocytes in response to AβOs induce pSerSTAT3 nuclear depletion, we used conditioned medium derived from AβOs-treated astrocyte cultures. Treatment of astrocyte-poor neuronal cultures with this medium caused pSerSTAT3 nuclear depletion but did not modify overall STAT3 levels. Extracellular catalase prevented the pSerSTAT3 nuclear depletion caused by astrocyte-conditioned medium, indicating that reactive oxygen species (ROS) mediate this response. This conditioned medium also increased neuronal oxidative tone, leading to a ryanodine-sensitive intracellular calcium signal that proved to be essential for pSerSTAT3 nuclear depletion. In addition, this depletion decreased BCL2 and Survivin transcription and significantly increased BAX/BCL2 ratio. This is the first description that ROS generated by AβOs-treated astrocytes and neuronal calcium signals jointly regulate pSerSTAT3 nuclear distribution in neurons. We propose that astrocytes release ROS in response to AβOs, which by increasing neuronal oxidative tone, generate calcium signals that cause pSerSTAT3 nuclear depletion and loss of STAT3 protective transcriptional activity.
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Affiliation(s)
- Yorka Muñoz
- Department of Biology, Faculty of Sciences,Universidad de Chile, Santiago, Chile
| | - Andrea C Paula-Lima
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile.
| | - Marco T Núñez
- Department of Biology, Faculty of Sciences,Universidad de Chile, Santiago, Chile.
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Sánchez G, Araneda F, Peña JP, Finkelstein JP, Riquelme JA, Montecinos L, Barrientos G, Llanos P, Pedrozo Z, Said M, Bull R, Donoso P. High-Fat-Diet-Induced Obesity Produces Spontaneous Ventricular Arrhythmias and Increases the Activity of Ryanodine Receptors in Mice. Int J Mol Sci 2018; 19:ijms19020533. [PMID: 29439404 PMCID: PMC5855755 DOI: 10.3390/ijms19020533] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 01/26/2018] [Accepted: 02/07/2018] [Indexed: 12/27/2022] Open
Abstract
Ventricular arrhythmias are a common cause of sudden cardiac death, and their occurrence is higher in obese subjects. Abnormal gating of ryanodine receptors (RyR2), the calcium release channels of the sarcoplasmic reticulum, can produce ventricular arrhythmias. Since obesity promotes oxidative stress and RyR2 are redox-sensitive channels, we investigated whether the RyR2 activity was altered in obese mice. Mice fed a high fat diet (HFD) became obese after eight weeks and exhibited a significant increase in the occurrence of ventricular arrhythmias. Single RyR2 channels isolated from the hearts of obese mice were more active in planar bilayers than those isolated from the hearts of the control mice. At the molecular level, RyR2 channels from HFD-fed mice had substantially fewer free thiol residues, suggesting that redox modifications were responsible for the higher activity. Apocynin, provided in the drinking water, completely prevented the appearance of ventricular arrhythmias in HFD-fed mice, and normalized the activity and content of the free thiol residues of the protein. HFD increased the expression of NOX4, an isoform of NADPH oxidase, in the heart. Our results suggest that HFD increases the activity of RyR2 channels via a redox-dependent mechanism, favoring the appearance of ventricular arrhythmias.
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Affiliation(s)
- Gina Sánchez
- Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile.
| | - Felipe Araneda
- Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile.
| | - Juan Pedro Peña
- Escuela de Ciencias Veterinarias, Universidad de Viña del Mar, 2572007 Viña del Mar, Valparaíso, Chile.
| | - José Pablo Finkelstein
- Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile.
| | - Jaime A Riquelme
- Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, 8380494 Santiago, Chile.
| | - Luis Montecinos
- Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile.
| | - Genaro Barrientos
- Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile.
| | - Paola Llanos
- Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, 8380492 Santiago, Chile.
| | - Zully Pedrozo
- Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile.
- Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, 8380494 Santiago, Chile.
| | - Matilde Said
- Centro de Investigaciones Cardiovasculares, CCT-CONICET La Plata, Facultad de Medicina, Universidad Nacional de La Plata, 1900 La Plata, Argentina.
| | - Ricardo Bull
- Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile.
| | - Paulina Donoso
- Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile.
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Regulation of protein function by S-nitrosation and S-glutathionylation: processes and targets in cardiovascular pathophysiology. Biol Chem 2017; 398:1267-1293. [DOI: 10.1515/hsz-2017-0150] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 08/07/2017] [Indexed: 02/07/2023]
Abstract
AbstractDecades of chemical, biochemical and pathophysiological research have established the relevance of post-translational protein modifications induced by processes related to oxidative stress, with critical reflections on cellular signal transduction pathways. A great deal of the so-called ‘redox regulation’ of cell function is in fact mediated through reactions promoted by reactive oxygen and nitrogen species on more or less specific aminoacid residues in proteins, at various levels within the cell machinery. Modifications involving cysteine residues have received most attention, due to the critical roles they play in determining the structure/function correlates in proteins. The peculiar reactivity of these residues results in two major classes of modifications, with incorporation of NO moieties (S-nitrosation, leading to formation of proteinS-nitrosothiols) or binding of low molecular weight thiols (S-thionylation, i.e. in particularS-glutathionylation,S-cysteinylglycinylation andS-cysteinylation). A wide array of proteins have been thus analyzed in detail as far as their susceptibility to either modification or both, and the resulting functional changes have been described in a number of experimental settings. The present review aims to provide an update of available knowledge in the field, with a special focus on the respective (sometimes competing and antagonistic) roles played by proteinS-nitrosations andS-thionylations in biochemical and cellular processes specifically pertaining to pathogenesis of cardiovascular diseases.
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Mallet RT, Olivencia-Yurvati AH, Bünger R. Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application. Exp Biol Med (Maywood) 2017; 243:198-210. [PMID: 29154687 DOI: 10.1177/1535370217743919] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cardiac contractile function is adenosine-5'-triphosphate (ATP)-intensive, and the myocardium's high demand for oxygen and energy substrates leaves it acutely vulnerable to interruptions in its blood supply. The myriad cardioprotective properties of the natural intermediary metabolite pyruvate make it a potentially powerful intervention against the complex injury cascade ignited by myocardial ischemia-reperfusion. A readily oxidized metabolic substrate, pyruvate augments myocardial free energy of ATP hydrolysis to a greater extent than the physiological fuels glucose, lactate and fatty acids, particularly when it is provided at supra-physiological plasma concentrations. Pyruvate also exerts antioxidant effects by detoxifying reactive oxygen and nitrogen intermediates, and by increasing nicotinamide adenine dinucleotide phosphate reduced form (NADPH) production to maintain glutathione redox state. These enhancements of free energy and antioxidant defenses combine to augment sarcoplasmic reticular Ca2+ release and re-uptake central to cardiac mechanical performance and to restore β-adrenergic signaling of ischemically stunned myocardium. By minimizing Ca2+ mismanagement and oxidative stress, pyruvate suppresses inflammation in post-ischemic myocardium. Thus, pyruvate administration stabilized cardiac performance, augmented free energy of ATP hydrolysis and glutathione redox systems, and/or quelled inflammation in a porcine model of cardiopulmonary bypass, a canine model of cardiac arrest-resuscitation, and a caprine model of hypovolemia and hindlimb ischemia-reperfusion. Pyruvate's myriad benefits in preclinical models provide the mechanistic framework for its clinical application as metabolic support for myocardium at risk. Phase one trials have demonstrated pyruvate's safety and efficacy for intravenous resuscitation for septic shock, intracoronary infusion for heart failure and as a component of cardioplegia for cardiopulmonary bypass. The favorable outcomes of these trials, which argue for expanded, phase three investigations of pyruvate therapy, mirror findings in isolated, perfused hearts, underscoring the pivotal role of preclinical research in identifying clinical interventions for cardiovascular diseases. Impact statement This article reviews pyruvate's cardioprotective properties as an energy-yielding metabolic fuel, antioxidant and anti-inflammatory agent in mammalian myocardium. Preclinical research has shown these properties make pyruvate a powerful intervention to curb the complex injury cascade ignited by ischemia and reperfusion. In ischemically stunned isolated hearts and in large mammal models of cardiopulmonary bypass, cardiac arrest-resuscitation and hypovolemia, intracoronary pyruvate supports recovery of myocardial contractile function, intracellular Ca2+ homeostasis and free energy of ATP hydrolysis, and its antioxidant actions restore β-adrenergic signaling and suppress inflammation. The first clinical trials of pyruvate for cardiopulmonary bypass, fluid resuscitation and intracoronary intervention for congestive heart failure have been reported. Receiver operating characteristic analyses show remarkable concordance between pyruvate's beneficial functional and metabolic effects in isolated, perfused hearts and in patients recovering from cardiopulmonary bypass in which they received pyruvate- vs. L-lactate-fortified cardioplegia. This research exemplifies the translation of mechanism-oriented preclinical studies to clinical application and outcomes.
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Affiliation(s)
- Robert T Mallet
- 1 Department of Integrative Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107-2699, USA
| | - Albert H Olivencia-Yurvati
- 1 Department of Integrative Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107-2699, USA.,2 Department of Medical Education, University of North Texas Health Science Center, Fort Worth, TX 76107-2699, USA
| | - Rolf Bünger
- 3 Emeritus Member of the American Physiological Society, McLean, VA 22101, USA
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Berridge MJ. Vitamin D deficiency: infertility and neurodevelopmental diseases (attention deficit hyperactivity disorder, autism, and schizophrenia). Am J Physiol Cell Physiol 2017; 314:C135-C151. [PMID: 29070492 DOI: 10.1152/ajpcell.00188.2017] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The process of development depends on a number of signaling systems that regulates the progressive sequence of developmental events. Infertility and neurodevelopmental diseases, such as attention deficit hyperactivity disorder, autism spectrum disorders, and schizophrenia, are caused by specific alterations in these signaling processes. Calcium signaling plays a prominent role throughout development beginning at fertilization and continuing through early development, implantation, and organ differentiation such as heart and brain development. Vitamin D plays a major role in regulating these signaling processes that control development. There is an increase in infertility and an onset of neurodevelopmental diseases when vitamin D is deficient. The way in which vitamin D deficiency acts to alter development is a major feature of this review. One of the primary functions of vitamin D is to maintain the phenotypic stability of both the Ca2+ and redox signaling pathways that play such a key role throughout development.
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Affiliation(s)
- Michael J Berridge
- Laboratory of Molecular Signalling, The Babraham Institute , Cambridge , United Kingdom
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Berridge MJ. Vitamin D, reactive oxygen species and calcium signalling in ageing and disease. Philos Trans R Soc Lond B Biol Sci 2017; 371:rstb.2015.0434. [PMID: 27377727 DOI: 10.1098/rstb.2015.0434] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2016] [Indexed: 12/13/2022] Open
Abstract
Vitamin D is a hormone that maintains healthy cells. It functions by regulating the low resting levels of cell signalling components such as Ca(2+) and reactive oxygen species (ROS). Its role in maintaining phenotypic stability of these signalling pathways depends on the ability of vitamin D to control the expression of those components that act to reduce the levels of both Ca(2+) and ROS. This regulatory role of vitamin D is supported by both Klotho and Nrf2. A decline in the vitamin D/Klotho/Nrf2 regulatory network may enhance the ageing process, and this is well illustrated by the age-related decline in cognition in rats that can be reversed by administering vitamin D. A deficiency in vitamin D has also been linked to two of the major diseases in man: heart disease and Alzheimer's disease (AD). In cardiac cells, this deficiency alters the Ca(2+) transients to activate the gene transcriptional events leading to cardiac hypertrophy and the failing heart. In the case of AD, it is argued that vitamin D deficiency results in the Ca(2+) landscape that initiates amyloid formation, which then elevates the resting level of Ca(2+) to drive the memory loss that progresses to neuronal cell death and dementia.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.
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A Feed-Forward Mechanism Involving the NOX Complex and RyR-Mediated Ca2+ Release During Axonal Specification. J Neurosci 2017; 36:11107-11119. [PMID: 27798190 DOI: 10.1523/jneurosci.1455-16.2016] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 09/06/2016] [Indexed: 01/16/2023] Open
Abstract
Physiological levels of ROS support neurite outgrowth and axonal specification, but the mechanisms by which ROS are able to shape neurons remain unknown. Ca2+, a broad intracellular second messenger, promotes both Rac1 activation and neurite extension. Ca2+ release from the endoplasmic reticulum, mediated by both the IP3R1 and ryanodine receptor (RyR) channels, requires physiological ROS levels that are mainly sustained by the NADPH oxidase (NOX) complex. In this work, we explore the contribution of the link between NOX and RyR-mediated Ca2+ release toward axonal specification of rat hippocampal neurons. Using genetic approaches, we find that NOX activation promotes both axonal development and Rac1 activation through a RyR-mediated mechanism, which in turn activates NOX through Rac1, one of the NOX subunits. Collectively, these data suggest a feedforward mechanism that integrates both NOX activity and RyR-mediated Ca2+ release to support cellular mechanisms involved in axon development. SIGNIFICANCE STATEMENT High levels of ROS are frequently associated with oxidative stress and disease. In contrast, physiological levels of ROS, mainly sustained by the NADPH oxidase (NOX) complex, promote neuronal development and axonal growth. However, the mechanisms by which ROS shape neurons have not been described. Our work suggests that NOX-derived ROS promote axonal growth by regulating Rac1 activity, a molecular determinant of axonal growth, through a ryanodine receptor (RyR)-mediated Ca2+ release mechanism. In addition, Rac1, one of the NOX subunits, was activated after RyR-mediated Ca2+ release, suggesting a feedforward mechanism between NOX and RyR. Collectively, our data suggest a novel mechanism that is instrumental in sustaining physiological levels of ROS required for axonal growth of hippocampal neurons.
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Abstract
Depression is caused by a change in neural activity resulting from an increase in glutamate that drives excitatory neurons and may be responsible for the decline in the activity and number of the GABAergic inhibitory neurons. This imbalance between the excitatory and inhibitory neurons may contribute to the onset of depression. At the cellular level there is an increase in the concentration of intracellular Ca2+ within the inhibitory neurons that is driven by an increase in entry through the NMDA receptors (NMDARs) and through activation of the phosphoinositide signaling pathway that generates inositol trisphosphate (InsP3) that releases Ca2+ from the internal stores. The importance of these two pathways in driving the elevation of Ca2+ is supported by the fact that depression can be alleviated by ketamine that inhibits the NMDARs and scopolamine that inhibits the M1 receptors that drive InsP3/Ca2+ pathway. This increase in Ca2+ not only contributes to depression but it may also explain why individuals with depression have a strong likelihood of developing Alzheimer's disease. The enhanced levels of Ca2+ may stimulate the formation of Aβ to initiate the onset and progression of Alzheimer's disease. Just how vitamin D acts to reduce depression is unclear. The phenotypic stability hypothesis argues that vitamin D acts by reducing the increased neuronal levels of Ca2+ that are driving depression. This action of vitamin D depends on its function to maintain the expression of the Ca2+ pumps and buffers that reduce Ca2+ levels, which may explain how it acts to reduce the onset of depression.
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Affiliation(s)
- Michael J Berridge
- Emeritus Babraham Fellow, The Babraham Institute, Cambridge, United Kingdom
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37
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Vitamin D deficiency and diabetes. Biochem J 2017; 474:1321-1332. [DOI: 10.1042/bcj20170042] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 02/10/2017] [Accepted: 02/13/2017] [Indexed: 02/06/2023]
Abstract
Vitamin D deficiency has been linked to the onset of diabetes. This review summarizes the role of Vitamin D in maintaining the normal release of insulin by the pancreatic beta cells (β-cells). Diabetes is initiated by the onset of insulin resistance. The β-cells can overcome this resistance by releasing more insulin, thus preventing hyperglycaemia. However, as this hyperactivity increases, the β-cells experience excessive Ca2+ and reactive oxygen species (ROS) signalling that results in cell death and the onset of diabetes. Vitamin D deficiency contributes to both the initial insulin resistance and the subsequent onset of diabetes caused by β-cell death. Vitamin D acts to reduce inflammation, which is a major process in inducing insulin resistance. Vitamin D maintains the normal resting levels of both Ca2+ and ROS that are elevated in the β-cells during diabetes. Vitamin D also has a very significant role in maintaining the epigenome. Epigenetic alterations are a feature of diabetes by which many diabetes-related genes are inactivated by hypermethylation. Vitamin D acts to prevent such hypermethylation by increasing the expression of the DNA demethylases that prevent hypermethylation of multiple gene promoter regions of many diabetes-related genes. What is remarkable is just how many cellular processes are maintained by Vitamin D. When Vitamin D is deficient, many of these processes begin to decline and this sets the stage for the onset of diseases such as diabetes.
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Matecki S, Dridi H, Jung B, Saint N, Reiken SR, Scheuermann V, Mrozek S, Santulli G, Umanskaya A, Petrof BJ, Jaber S, Marks AR, Lacampagne A. Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation. Proc Natl Acad Sci U S A 2016; 113:9069-74. [PMID: 27457930 PMCID: PMC4987795 DOI: 10.1073/pnas.1609707113] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ventilator-induced diaphragmatic dysfunction (VIDD) refers to the diaphragm muscle weakness that occurs following prolonged controlled mechanical ventilation (MV). The presence of VIDD impedes recovery from respiratory failure. However, the pathophysiological mechanisms accounting for VIDD are still not fully understood. Here, we show in human subjects and a mouse model of VIDD that MV is associated with rapid remodeling of the sarcoplasmic reticulum (SR) Ca(2+) release channel/ryanodine receptor (RyR1) in the diaphragm. The RyR1 macromolecular complex was oxidized, S-nitrosylated, Ser-2844 phosphorylated, and depleted of the stabilizing subunit calstabin1, following MV. These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by MV and stimulation of adrenergic signaling resulting from the anesthesia. We demonstrate in the murine model that such abnormal resting SR Ca(2+) leak resulted in reduced contractile function and muscle fiber atrophy for longer duration of MV. Treatment with β-adrenergic antagonists or with S107, a small molecule drug that stabilizes the RyR1-calstabin1 interaction, prevented VIDD. Diaphragmatic dysfunction is common in MV patients and is a major cause of failure to wean patients from ventilator support. This study provides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD (i.e., loss of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention.
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Affiliation(s)
- Stefan Matecki
- Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France
| | - Haikel Dridi
- Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France
| | - Boris Jung
- Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France; Department of Anesthesiology and Critical Care Medicine, St. Eloi Teaching Hospital, 34295 Montpellier, France
| | - Nathalie Saint
- Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France
| | - Steven R Reiken
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; The Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032
| | - Valérie Scheuermann
- Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France
| | - Ségolène Mrozek
- Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France
| | - Gaetano Santulli
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; The Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032
| | - Alisa Umanskaya
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; The Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032
| | - Basil J Petrof
- Meakins-Christie Laboratories, McGill University and McGill University Hospital Research Institute, Montreal, QC H2X 2P2, Canada
| | - Samir Jaber
- Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France; Department of Anesthesiology and Critical Care Medicine, St. Eloi Teaching Hospital, 34295 Montpellier, France
| | - Andrew R Marks
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; The Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
| | - Alain Lacampagne
- Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France;
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Bogdanova A, Petrushanko IY, Hernansanz-Agustín P, Martínez-Ruiz A. "Oxygen Sensing" by Na,K-ATPase: These Miraculous Thiols. Front Physiol 2016; 7:314. [PMID: 27531981 PMCID: PMC4970491 DOI: 10.3389/fphys.2016.00314] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 07/12/2016] [Indexed: 12/16/2022] Open
Abstract
Control over the Na,K-ATPase function plays a central role in adaptation of the organisms to hypoxic and anoxic conditions. As the enzyme itself does not possess O2 binding sites its "oxygen-sensitivity" is mediated by a variety of redox-sensitive modifications including S-glutathionylation, S-nitrosylation, and redox-sensitive phosphorylation. This is an overview of the current knowledge on the plethora of molecular mechanisms tuning the activity of the ATP-consuming Na,K-ATPase to the cellular metabolic activity. Recent findings suggest that oxygen-derived free radicals and H2O2, NO, and oxidized glutathione are the signaling messengers that make the Na,K-ATPase "oxygen-sensitive." This very ancient signaling pathway targeting thiols of all three subunits of the Na,K-ATPase as well as redox-sensitive kinases sustains the enzyme activity at the "optimal" level avoiding terminal ATP depletion and maintaining the transmembrane ion gradients in cells of anoxia-tolerant species. We acknowledge the complexity of the underlying processes as we characterize the sources of reactive oxygen and nitrogen species production in hypoxic cells, and identify their targets, the reactive thiol groups which, upon modification, impact the enzyme activity. Structured accordingly, this review presents a summary on (i) the sources of free radical production in hypoxic cells, (ii) localization of regulatory thiols within the Na,K-ATPase and the role reversible thiol modifications play in responses of the enzyme to a variety of stimuli (hypoxia, receptors' activation) (iii) redox-sensitive regulatory phosphorylation, and (iv) the role of fine modulation of the Na,K-ATPase function in survival success under hypoxic conditions. The co-authors attempted to cover all the contradictions and standing hypotheses in the field and propose the possible future developments in this dynamic area of research, the importance of which is hard to overestimate. Better understanding of the processes underlying successful adaptation strategies will make it possible to harness them and use for treatment of patients with stroke and myocardial infarction, sleep apnoea and high altitude pulmonary oedema, and those undergoing surgical interventions associated with the interruption of blood perfusion.
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Affiliation(s)
- Anna Bogdanova
- Institute of Veterinary Physiology, Vetsuisse Faculty and the Zurich Center for Integrative Human Physiology (ZIHP), University of ZurichZurich, Switzerland
| | - Irina Y. Petrushanko
- Engelhardt Institute of Molecular Biology, Russian Academy of SciencesMoscow, Russia
| | - Pablo Hernansanz-Agustín
- Servicio de Inmunología, Instituto de Investigación Sanitaria Princesa (IIS-IP), Hospital Universitario de La PrincesaMadrid, Spain
- Departamento de Bioquímica, Universidad Autónoma de MadridMadrid, Spain
| | - Antonio Martínez-Ruiz
- Servicio de Inmunología, Instituto de Investigación Sanitaria Princesa (IIS-IP), Hospital Universitario de La PrincesaMadrid, Spain
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Kiselyov K, Muallem S. ROS and intracellular ion channels. Cell Calcium 2016; 60:108-14. [PMID: 26995054 DOI: 10.1016/j.ceca.2016.03.004] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 03/03/2016] [Accepted: 03/04/2016] [Indexed: 12/15/2022]
Abstract
Oxidative stress is a well-known driver of numerous pathological processes involving protein and lipid peroxidation and DNA damage. The resulting increase of pro-apoptotic pressure drives tissue damage in a host of conditions, including ischemic stroke and reperfusion injury, diabetes, death in acute pancreatitis and neurodegenerative diseases. Somewhat less frequently discussed, but arguably as important, is the signaling function of oxidative stress stemming from the ability of oxidative stress to modulate ion channel activity. The evidence for the modulation of the intracellular ion channels and transporters by oxidative stress is constantly emerging and such evidence suggests new regulatory and pathological circuits that can be explored towards new treatments for diseases in which oxidative stress is an issue. In this review we summarize the current knowledge on the effects of oxidative stress on the intracellular ion channels and transporters and their role in cell function.
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Affiliation(s)
- Kirill Kiselyov
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States; Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch NIH, NIDCR, Bethesda, MD 20892, United States.
| | - Shmuel Muallem
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States; Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch NIH, NIDCR, Bethesda, MD 20892, United States.
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Cheng YS, Dai DZ, Dai Y, Zhu DD, Liu BC. Exogenous hydrogen sulphide ameliorates diabetic cardiomyopathy in rats by reversing disordered calcium-handling system in sarcoplasmic reticulum. ACTA ACUST UNITED AC 2016; 68:379-88. [PMID: 26968978 DOI: 10.1111/jphp.12517] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 12/13/2015] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Hydrogen sulphide (H2 S) has been found to be involved in cardiovascular diseases, but the exact mechanism has not been clarified. The purpose of this study was to investigate whether sodium hydrogen sulphide (NaHS), the donor of H2 S, can improve diabetic cardiomyopathy by reversing disordered calcium-handling system in sarcoplasmic reticulum (SR). METHODS Sprague Dawley rats were injected with streptozotocin (STZ, 60 mg/kg, i.p.) to build diabetic model. Treatment groups included: aminoguanidine group (AG, 100 mg/kg, p.o.) and NaHS group (5 mg/kg per day, s.c.). KEY FINDINGS Cardiac dysfunction and myocardial hypertrophy were found in diabetic model (DM) group, along with increased ROS levels and upregulated mRNA and protein expressions of NADPH p22(phox) , endothelin A receptor (ETA ) and protein kinase Cε (PKCε). Expressions of calcium-handling proteins in SR including FK506-binding proteins (FKBP12.6), sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) and calsequestrin 2 (CASQ2) were downregulated in DM group, accompanied by elevated concentration of diastolic free calcium in high glucose-incubated cardiomyocytes, indicating of calcium leak. After treated by NaHS, these abnormalities were attenuated significantly. CONCLUSIONS Exogenous H2 S played a protective role in diabetic cardiomyopathy by inhibiting abnormal calcium-handling system in SR and ET-NADPH oxidase-PKCε pathway.
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Affiliation(s)
- Yu-Si Cheng
- Institute of Nephrology, Zhong Da Hospital, Medical School of Southeast University, Nanjing, China
| | - De-Zai Dai
- Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Yin Dai
- Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Dong-Dong Zhu
- Institute of Nephrology, Zhong Da Hospital, Medical School of Southeast University, Nanjing, China
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhong Da Hospital, Medical School of Southeast University, Nanjing, China
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Patel R, Sesti F. Oxidation of ion channels in the aging nervous system. Brain Res 2016; 1639:174-85. [PMID: 26947620 DOI: 10.1016/j.brainres.2016.02.046] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 02/24/2016] [Accepted: 02/25/2016] [Indexed: 12/19/2022]
Abstract
Ion channels are integral membrane proteins that allow passive diffusion of ions across membranes. In neurons and in other excitable cells, the harmonious coordination between the numerous types of ion channels shape and propagate electrical signals. Increased accumulation of reactive oxidative species (ROS), and subsequent oxidation of proteins, including ion channels, is a hallmark feature of aging and may contribute to cell failure as a result. In this review we discuss the effects of ROS on three major types of ion channels of the central nervous system, namely the potassium (K(+)), calcium (Ca(2+)) and sodium (Na(+)) channels. We examine two general mechanisms through which ROS affect ion channels: via direct oxidation of specific residues and via indirect interference of pathways that regulate the channels. The overall status of the present studies indicates that the interaction of ion channels with ROS is multimodal and pervasive in the central nervous system and likely constitutes a general mechanism of aging susceptibility.
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Affiliation(s)
- Rahul Patel
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, 683 Hoes Lane West, Piscataway, NJ 08854, USA
| | - Federico Sesti
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, 683 Hoes Lane West, Piscataway, NJ 08854, USA.
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Tuncay E, Turan B. Intracellular Zn(2+) Increase in Cardiomyocytes Induces both Electrical and Mechanical Dysfunction in Heart via Endogenous Generation of Reactive Nitrogen Species. Biol Trace Elem Res 2016; 169:294-302. [PMID: 26138011 DOI: 10.1007/s12011-015-0423-3] [Citation(s) in RCA: 31] [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: 04/23/2015] [Accepted: 06/23/2015] [Indexed: 12/23/2022]
Abstract
Oxidants increase intracellular free Zn(2+) concentration ([Zn(2+)]i) in ventricular myocytes, which contributes to oxidant-induced alterations in excitation-contraction coupling (ECC). However, it is not clear whether increased [Zn(2+)]i in cardiomyocytes via increased reactive nitrogen species (RNS) has a role on heart function under pathological conditions, such as hyperglycemia. In this study, first we aimed to investigate the role of increased [Zn(2+)]i under in vitro condition in the development of both electrical and mechanical dysfunction of isolated papillary muscle strips from rat heart via exposed samples to a Zn(2+)-ionophore (Zn-pyrithione; 1 μM) for 20 min. Under simultaneous measurement of intracellular action potential and contractile activity in these preparations, Zn-pyrithione exposure caused marked prolongation in action potential repolarization phase and slowdown in both contraction and relaxation rates of twitch activity. Second, in order to demonstrate an association between increased [Zn(2+)]i and increased RNS, we monitored intracellular [Zn(2+)]i under an acute exposure of nitric oxide (NO) donor sodium nitroprusside, SNP, in freshly isolated quiescent cardiomyocytes loaded with FluoZin-3. Resting level of free Zn(2+) is significantly higher in cardiomyocytes under hyperglycemic condition compared to those of the controls, which seems to be associated with increased level of RNS production in hyperglycemic cardiomyocytes. Western blot analysis showed that Zn-pyrithione exposure induced a marked decrease in the activity of protein phosphatase 1 and 2A, member of macromolecular protein complex of cardiac ryanodine receptors, RyR2, besides significant increase in the phosphorylation level of extracellular signal-regulated kinase1/2 as a concentration-dependent manner. Overall, the present data demonstrated that there is a cross-relationship between increased RNS production and increased [Zn(2+)]i level in cardiomyocytes under pathological conditions such as hyperglycemia.
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Affiliation(s)
- Erkan Tuncay
- Department of Biophysics, Ankara University Faculty of Medicine, 06100, Ankara, Turkey
| | - Belma Turan
- Department of Biophysics, Ankara University Faculty of Medicine, 06100, Ankara, Turkey.
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HNO/Thiol Biology as a Therapeutic Target. OXIDATIVE STRESS IN APPLIED BASIC RESEARCH AND CLINICAL PRACTICE 2016. [DOI: 10.1007/978-3-319-30705-3_14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Diebold BA, Smith SM, Li Y, Lambeth JD. NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress. Antioxid Redox Signal 2015; 23:375-405. [PMID: 24512192 PMCID: PMC4545678 DOI: 10.1089/ars.2014.5862] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 02/08/2014] [Indexed: 12/27/2022]
Abstract
SIGNIFICANCE NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. RECENT ADVANCES Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. CRITICAL ISSUES Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. FUTURE DIRECTIONS NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents.
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Affiliation(s)
- Becky A. Diebold
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Susan M.E. Smith
- Department of Biology and Physics, Kennesaw State University, Kennesaw, Georgia
| | - Yang Li
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - J. David Lambeth
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
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Berridge MJ. Vitamin D cell signalling in health and disease. Biochem Biophys Res Commun 2015; 460:53-71. [PMID: 25998734 DOI: 10.1016/j.bbrc.2015.01.008] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 01/05/2015] [Indexed: 12/13/2022]
Abstract
Vitamin D deficiency has been linked to many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), hypertension and cardiovascular disease. A Vitamin D phenotypic stability hypothesis, which is developed in this review, attempts to describe how this vital hormone acts to maintain healthy cellular functions. This role of Vitamin D as a guardian of phenotypic stability seems to depend on its ability to maintain the redox and Ca(2+) signalling systems. It is argued that its primary action is to maintain the expression of those signalling components responsible for stabilizing the low resting state of these two signalling pathways. This phenotypic stability role is facilitated through the ability of vitamin D to increase the expression of both Nrf2 and the anti-ageing protein Klotho, which are also major regulators of Ca(2+) and redox signalling. A decline in Vitamin D levels will lead to a decline in the stability of this regulatory signalling network and may account for why so many of the major diseases in man, which have been linked to vitamin D deficiency, are associated with a dysregulation in both ROS and Ca(2+) signalling.
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Deletioglu V, Tuncay E, Toy A, Atalay M, Turan B. Immuno-spin trapping detection of antioxidant/pro-oxidant properties of zinc or selenium on DNA and protein radical formation via hydrogen peroxide. Mol Cell Biochem 2015; 409:23-31. [DOI: 10.1007/s11010-015-2508-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 07/04/2015] [Indexed: 11/29/2022]
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Thakur A, Alam MJ, Ajayakumar MR, Ghaskadbi S, Sharma M, Goswami SK. Norepinephrine-induced apoptotic and hypertrophic responses in H9c2 cardiac myoblasts are characterized by different repertoire of reactive oxygen species generation. Redox Biol 2015; 5:243-252. [PMID: 26070033 PMCID: PMC4477046 DOI: 10.1016/j.redox.2015.05.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 05/26/2015] [Indexed: 01/04/2023] Open
Abstract
Despite recent advances, the role of ROS in mediating hypertrophic and apoptotic responses in cardiac myocytes elicited by norepinephrine (NE) is rather poorly understood. We demonstrate through our experiments that H9c2 cardiac myoblasts treated with 2 µM NE (hypertrophic dose) generate DCFH-DA positive ROS only for 2 h; while those treated with 100 µM NE (apoptotic dose) sustains generation for 48 h, followed by apoptosis. Though the levels of DCFH fluorescence were comparable at early time points in the two treatment sets, its quenching by DPI, catalase and MnTmPyP suggested the existence of a different repertoire of ROS. Both doses of NE also induced moderate levels of H2O2 but with different kinetics. Sustained but intermittent generation of highly reactive species detectable by HPF was seen in both treatment sets but no peroxynitrite was generated in either conditions. Sustained generation of hydroxyl radicals with no appreciable differences were noticed in both treatment sets. Nevertheless, despite similar profile of ROS generation between the two conditions, extensive DNA damage as evident from the increase in 8-OH-dG content, formation of γ-H2AX and PARP cleavage was seen only in cells treated with the higher dose of NE. We therefore conclude that hypertrophic and apoptotic doses of NE generate distinct but comparable repertoire of ROS/RNS leading to two very distinct downstream responses.
H9c2 myoblasts upon treatment with 2 and 100 µM NE induces hypertrophy and apoptosis. Both treatments show comparable levels of DCFH fluorescence with different kinetics. Both treatments show comparable levels of HPF fluorescence in an oscillating manner. More hydroxyl radical was generated in 100 µM NE treated set. DNA damage and apoptosis occurs only in 100 µM NE treated sets.
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Affiliation(s)
- Anita Thakur
- Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Md Jahangir Alam
- School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - M R Ajayakumar
- School of Physical Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | | | - Manish Sharma
- Defence Institute of Physiology & Allied Sciences, New Delhi 110054, India
| | - Shyamal K Goswami
- School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
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Roussel J, Thireau J, Brenner C, Saint N, Scheuermann V, Lacampagne A, Le Guennec JY, Fauconnier J. Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase. Biochim Biophys Acta Mol Basis Dis 2015; 1852:749-58. [DOI: 10.1016/j.bbadis.2015.01.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 01/16/2015] [Accepted: 01/18/2015] [Indexed: 12/30/2022]
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Mattiazzi A, Bassani RA, Escobar AL, Palomeque J, Valverde CA, Vila Petroff M, Bers DM. Chasing cardiac physiology and pathology down the CaMKII cascade. Am J Physiol Heart Circ Physiol 2015; 308:H1177-91. [PMID: 25747749 DOI: 10.1152/ajpheart.00007.2015] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 02/16/2015] [Indexed: 11/22/2022]
Abstract
Calcium dynamics is central in cardiac physiology, as the key event leading to the excitation-contraction coupling (ECC) and relaxation processes. The primary function of Ca(2+) in the heart is the control of mechanical activity developed by the myofibril contractile apparatus. This key role of Ca(2+) signaling explains the subtle and critical control of important events of ECC and relaxation, such as Ca(2+) influx and SR Ca(2+) release and uptake. The multifunctional Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a signaling molecule that regulates a diverse array of proteins involved not only in ECC and relaxation but also in cell death, transcriptional activation of hypertrophy, inflammation, and arrhythmias. CaMKII activity is triggered by an increase in intracellular Ca(2+) levels. This activity can be sustained, creating molecular memory after the decline in Ca(2+) concentration, by autophosphorylation of the enzyme, as well as by oxidation, glycosylation, and nitrosylation at different sites of the regulatory domain of the kinase. CaMKII activity is enhanced in several cardiac diseases, altering the signaling pathways by which CaMKII regulates the different fundamental proteins involved in functional and transcriptional cardiac processes. Dysregulation of these pathways constitutes a central mechanism of various cardiac disease phenomena, like apoptosis and necrosis during ischemia/reperfusion injury, digitalis exposure, post-acidosis and heart failure arrhythmias, or cardiac hypertrophy. Here we summarize significant aspects of the molecular physiology of CaMKII and provide a conceptual framework for understanding the role of the CaMKII cascade on Ca(2+) regulation and dysregulation in cardiac health and disease.
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Affiliation(s)
- Alicia Mattiazzi
- Centro de Investigaciones Cardiovasculares, The National Scientific and Technical Research Council-La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina;
| | - Rosana A Bassani
- Centro de Engenharia Biomédica, Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Ariel L Escobar
- Biological Engineering and Small Scale Technologies, School of Engineering, University of California, Merced, California; and
| | - Julieta Palomeque
- Centro de Investigaciones Cardiovasculares, The National Scientific and Technical Research Council-La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Carlos A Valverde
- Centro de Investigaciones Cardiovasculares, The National Scientific and Technical Research Council-La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Martín Vila Petroff
- Centro de Investigaciones Cardiovasculares, The National Scientific and Technical Research Council-La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Donald M Bers
- Department of Pharmacology, University of California Davis, Davis, California
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