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Mueller BJ, Roberts MD, Mobley CB, Judd RL, Kavazis AN. Nitric oxide in exercise physiology: past and present perspectives. Front Physiol 2025; 15:1504978. [PMID: 39850450 PMCID: PMC11754211 DOI: 10.3389/fphys.2024.1504978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 12/17/2024] [Indexed: 01/25/2025] Open
Abstract
Nitric oxide (NO) is a ubiquitous signaling molecule known to modulate various physiological processes, with specific implications in skeletal muscle and broader applications in exercise performance. This review focuses on the modulation of skeletal muscle function, mitochondrial adaptation and function, redox state by NO, and the effect of nitrate supplementation on exercise performance. In skeletal muscle function, NO is believed to increase the maximal shortening velocity and peak power output of muscle fibers. However, its effect on submaximal contraction is still undetermined. In mitochondria, NO may stimulate biogenesis and affect respiratory efficiency. NO also plays a role in the redox state within the skeletal muscle, partially through its interaction with respiratory chain enzymes and transcriptional regulators of antioxidant production. Nitrate supplementation leads to an increased bioavailability of NO in skeletal muscle. Thus, nitrate supplementation has been investigated for its ability to impact performance outcomes in endurance and resistance exercise. The effect of nitrate supplementation on endurance exercise is currently indecisive, although evidence indicates that it may extend the time to exhaustion in endurance exercise. Alternatively, the effect of nitrate supplementation on resistance exercise performance has been less studied. Limited research indicates that nitrate supplementation may improve repetitions to failure. Further research is needed to investigate the influence of training status, age, sex, and duration of supplementation to further elucidate the impact of nitrate supplementation on exercise performance.
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Affiliation(s)
| | | | | | - Robert L. Judd
- Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, AL, United States
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2
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Vrooman OPJ, van Kerrebroeck PEV, van Balken MR, van Koeveringe GA, Rahnama'i MS. Nocturia and obstructive sleep apnoea. Nat Rev Urol 2024; 21:735-753. [PMID: 38783115 DOI: 10.1038/s41585-024-00887-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2024] [Indexed: 05/25/2024]
Abstract
Nocturia, the need to urinate at night, is a common symptom in patients with obstructive sleep apnoea (OSA). Continuous positive airway pressure treatment can reduce nocturia in some patients, but the underlying mechanisms are complex and not fully understood. OSA affects the autonomic nervous system, oxidative stress and endothelial damage. Furthermore, the commonly held theory attributing polyuria to a false signal of cardiac overload and response natriuresis has limitations. A comprehensive approach to the management of nocturia in OSA, considering factors such as comorbidities, medication use, alcohol consumption and lifestyle, is needed. Effective management of nocturia in OSA requires a multidisciplinary approach, and urologists should be aware of the potential effect of OSA on physiology and refer patients for further testing at a sleep centre. In addition to continuous positive airway pressure, other interventions such as oral appliances and surgical obstruction treatment could be beneficial for some patients. Overall, understanding the complex interplay between OSA and nocturia is crucial for optimizing patient outcomes.
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Affiliation(s)
- Olaf P J Vrooman
- Department of Urology, Hospital Rijnstate Arnhem, Arnhem, Netherlands.
| | | | | | | | - Mohammad S Rahnama'i
- Department of Urology Nij Smellinghe Hospital, Drachten, Netherlands
- Society of Urological research and education (SURE), Maastricht, Netherlands
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3
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Stoodley P, Toelke N, Schwermer C, de Beer D. Bioenergetics of simultaneous oxygen and nitrate respiration and nitric oxide production in a Pseudomonas aeruginosa agar colony biofilm. Biofilm 2024; 7:100181. [PMID: 38425549 PMCID: PMC10902143 DOI: 10.1016/j.bioflm.2024.100181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 01/09/2024] [Accepted: 02/01/2024] [Indexed: 03/02/2024] Open
Abstract
Pseudomonas aeruginosa is a biofilm forming pathogen commonly associated with infection of the cystic fibrosis (CF) lung, chronic wounds and indwelling medical devices. P. aeruginosa is a facultative aerobe that can use nitrate (NO3-) found in healthy and infected tissues and body fluids to generate energy through denitrification. Further, P. aeruginosa the expression of denitrification genes has been found in specimens from people with CF. The main aim of this study was to determine the relative energy contribution of oxygen (O2) respiration and denitrification in single Pseudomonas aeruginosa PAO1 biofilm colonies under different O2 concentrations to estimate the possible relative importance of these metabolic processes in the context of biofilm infections. We showed that the used strain PAO1 in biofilms denitrified with nitrous oxide (N2O), and not nitrogen (N2), as the end product in our incubations. From simultaneous O2 and N2O microprofiles measured with high spatial resolution by microsensors in agar colony biofilms under air, N2 and pure O2, the rates of aerobic respiration and denitrification were calculated and converted to ATP production rates. Denitrification occurred both in the oxic and anoxic zones, and became increasingly dominant with decreasing O2 concentrations. At O2 concentrations characteristic for tissues and wounds (20-60 μM), denitrification was responsible for 50% of the total energy conservation in the biofilm. In addition the formation of nitric oxide (NO), a precursor of N2O and an important regulator of many cellular processes, was strongly influenced by the local O2 concentrations. NO production was inhibited under pure O2, present under anoxia (∼1 μM) and remarkably high (up to 6 μM) under intermediate O2 levels, which can be found in infected tissues. Possible impacts of such NO levels on both the host and the biofilm bacteria are discussed.
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Affiliation(s)
- Paul Stoodley
- National Centre for Advanced Tribology at Southampton, (NCATS), Mechanical Engineering, University of Southampton, Southampton, SO17 1BJ, UK
- Department of Microbial Infection and Immunity, Department of Orthopaedics, The Ohio State University, 716 Biomedical Research Tower (BRT), 460 W 12th Ave, Columbus OH, 43210, United States
| | - Nina Toelke
- Max Planck Institute for Marine Microbiology (MPI), Microsensor Group and Molecular Ecology Group, Celsiusstrasse 1, D-28359, Bremen, Germany
| | - Carsten Schwermer
- Norwegian Institute for Water Research (NIVA), Gaustadalléen 21, NO-0349, Oslo, Norway
| | - Dirk de Beer
- Max Planck Institute for Marine Microbiology (MPI), Microsensor Group and Molecular Ecology Group, Celsiusstrasse 1, D-28359, Bremen, Germany
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Haynes V, Giulivi C. Calcium-Dependent Interaction of Nitric Oxide Synthase with Cytochrome c Oxidase: Implications for Brain Bioenergetics. Brain Sci 2023; 13:1534. [PMID: 38002494 PMCID: PMC10669843 DOI: 10.3390/brainsci13111534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Targeted nitric oxide production is relevant for maintaining cellular energy production, protecting against oxidative stress, regulating cell death, and promoting neuroprotection. This study aimed to characterize the putative interaction of nitric-oxide synthase with mitochondrial proteins. The primary finding of this study is that cytochrome c oxidase (CCO) subunit IV (CCOIV) is associated directly with NOS in brain mitochondria when calcium ions are present. The matrix side of CCOIV binds to the N-terminus of NOS, supported by the abrogation of the binding by antibodies towards the N-terminus of NOS. Evidence supporting the interaction between CCOIV and NOS was provided by the coimmunoprecipitation of NOS from detergent-solubilized whole rat brain mitochondria with antibodies to CCOIV and the coimmunoprecipitation of CCOIV from crude brain NOS preparations using antibodies to NOS. The CCOIV domain that interacts with NOS was identified using a series of overlapping peptides derived from the primary sequence of CCOIV. As calcium ions not only activate NOS, but also facilitate the docking of NOS to CCOIV, this study points to a dynamic mechanism of controlling the bioenergetics by calcium changes, thereby adapting bioenergetics to cellular demands.
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Affiliation(s)
- Virginia Haynes
- School of Veterinary Medicine, Department Molecular Biosciences, University of California Davis, Davis, CA 95616, USA
| | - Cecilia Giulivi
- School of Veterinary Medicine, Department Molecular Biosciences, University of California Davis, Davis, CA 95616, USA
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDH, University of California Davis, Sacramento, CA 95817, USA
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5
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Doulias PT, Yang H, Andreyev AY, Dolatabadi N, Scott H, K Raspur C, Patel PR, Nakamura T, Tannenbaum SR, Ischiropoulos H, Lipton SA. S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons. Cell Chem Biol 2023; 30:965-975.e6. [PMID: 37478858 PMCID: PMC10530441 DOI: 10.1016/j.chembiol.2023.06.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 03/16/2023] [Accepted: 06/16/2023] [Indexed: 07/23/2023]
Abstract
A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in activity inhibition assessed by carbon-labeled metabolic flux experiments. This inhibition principally affects α-ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing α-ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death. Our evidence indicates that aberrant S-nitrosylation of TCA cycle enzymes contributes to this bioenergetic failure.
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Affiliation(s)
- Paschalis-Thomas Doulias
- Children's Hospital of Philadelphia Departments of Pediatrics and Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Chemistry and University Research Center of Ioannina, University of Ioannina, 45110 Ioannina, Greece
| | - Hongmei Yang
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Changchun University of Chinese Medicine, Changchun 130021, China
| | - Alexander Y Andreyev
- Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Nima Dolatabadi
- Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Henry Scott
- Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Charlene K Raspur
- Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Parth R Patel
- Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Tomohiro Nakamura
- Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Steven R Tannenbaum
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Harry Ischiropoulos
- Children's Hospital of Philadelphia Departments of Pediatrics and Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Stuart A Lipton
- Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
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Identification of Body Size Determination Related Candidate Genes in Domestic Pig Using Genome-Wide Selection Signal Analysis. Animals (Basel) 2022; 12:ani12141839. [PMID: 35883386 PMCID: PMC9312078 DOI: 10.3390/ani12141839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/13/2022] [Accepted: 07/18/2022] [Indexed: 01/03/2023] Open
Abstract
This study aimed to identify the genes related to the body size of pigs by conducting genome-wide selection analysis (GWSA). We performed a GWSA scan on 50 pigs belonging to four small-bodied pig populations (Diannan small-eared pig, Bama Xiang pig, Wuzhishan pig, and Jeju black pig from South Korea) and 124 large-bodied pigs. We used the genetic parameters of the pairwise fixation index (FST) and π ratio (case/control) to screen candidate genome regions and genes related to body size. The results revealed 47,339,509 high-quality SNPs obtained from 174 individuals, while 280 interacting candidate regions were obtained from the top 1% signal windows of both parameters, along with 187 genes (e.g., ADCK4, AMDHD2, ASPN, ASS1, and ATP6V0C). The results of the candidate gene (CG) annotation showed that a series of CGs (e.g., MSTN, LTBP4, PDPK1, PKMYT1, ASS1, and STAT6) was enriched into the gene ontology terms. Moreover, molecular pathways, such as the PI3K-Akt, HIF-1, and AMPK signaling pathways, were verified to be related to body development. Overall, we identified a series of key genes that may be closely related to the body size of pigs, further elucidating the heredity basis of body shape determination in pigs and providing a theoretical reference for molecular breeding.
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The Relationship of Glutathione- S-Transferase and Multi-Drug Resistance-Related Protein 1 in Nitric Oxide (NO) Transport and Storage. Molecules 2021; 26:molecules26195784. [PMID: 34641326 PMCID: PMC8510172 DOI: 10.3390/molecules26195784] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/21/2021] [Accepted: 09/21/2021] [Indexed: 12/18/2022] Open
Abstract
Nitric oxide is a diatomic gas that has traditionally been viewed, particularly in the context of chemical fields, as a toxic, pungent gas that is the product of ammonia oxidation. However, nitric oxide has been associated with many biological roles including cell signaling, macrophage cytotoxicity, and vasodilation. More recently, a model for nitric oxide trafficking has been proposed where nitric oxide is regulated in the form of dinitrosyl-dithiol-iron-complexes, which are much less toxic and have a significantly greater half-life than free nitric oxide. Our laboratory has previously examined this hypothesis in tumor cells and has demonstrated that dinitrosyl-dithiol-iron-complexes are transported and stored by multi-drug resistance-related protein 1 and glutathione-S-transferase P1. A crystal structure of a dinitrosyl-dithiol-iron complex with glutathione-S-transferase P1 has been solved that demonstrates that a tyrosine residue in glutathione-S-transferase P1 is responsible for binding dinitrosyl-dithiol-iron-complexes. Considering the roles of nitric oxide in vasodilation and many other processes, a physiological model of nitric oxide transport and storage would be valuable in understanding nitric oxide physiology and pathophysiology.
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Acute Effects of Dietary Nitrate on Exercise Tolerance, Muscle Oxygenation, and Cardiovascular Function in Patients With Peripheral Arterial Disease. Int J Sport Nutr Exerc Metab 2021; 31:385-396. [PMID: 34284348 DOI: 10.1123/ijsnem.2021-0054] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/23/2021] [Accepted: 04/23/2021] [Indexed: 11/18/2022]
Abstract
Previous studies have used supplements to increase dietary nitrate intake in clinical populations. Little is known about whether effects can also be induced through vegetable consumption. Therefore, the aim of this study was to assess the impact of dietary nitrate, through nitrate-rich vegetables (NRV) and beetroot juice (BRJ) supplementation, on plasma nitrate and nitrite concentrations, exercise tolerance, muscle oxygenation, and cardiovascular function in patients with peripheral arterial disease. In a randomized crossover design, 18 patients with peripheral arterial disease (age: 73 ± 8 years) followed a nitrate intake protocol (∼6.5 mmol) through the consumption of NRV, BRJ, and nitrate-depleted BRJ (placebo). Blood samples were taken, blood pressure and arterial stiffness were measured in fasted state and 150 min after intervention. Each intervention was followed by a maximal walking exercise test to determine claudication onset time and peak walking time. Gastrocnemius oxygenation was measured by near-infrared spectroscopy. Blood samples were taken and blood pressure was measured 10 min after exercise. Mean plasma nitrate and nitrite concentrations increased (nitrate; Time × Intervention interaction; p < .001), with the highest concentrations after BRJ (494 ± 110 μmol/L) compared with NRV (202 ± 89 μmol/L) and placebo (80 ± 19 μmol/L; p < .001). Mean claudication onset time and peak walking time did not differ between NRV (413 ± 187 s and 745 ± 220 s, respectively), BRJ (392 ± 154 s and 746 ± 176 s), and placebo (403 ± 176 s and 696 ± 222 s) (p = .762 and p = .165, respectively). Gastrocnemius oxygenation, blood pressure, and arterial stiffness were not affected by the intervention. NRV and BRJ intake markedly increase plasma nitrate and nitrite, but this does not translate to improved exercise tolerance, muscle oxygenation, and/or cardiovascular function.
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9
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Krause BJ. Novel insights for the role of nitric oxide in placental vascular function during and beyond pregnancy. J Cell Physiol 2021; 236:7984-7999. [PMID: 34121195 DOI: 10.1002/jcp.30470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 01/02/2023]
Abstract
More than 30 years have passed since endothelial nitric oxide synthesis was described using the umbilical artery and vein endothelium. That seminal report set the cornerstone for unveiling the molecular aspects of endothelial function. In parallel, the understanding of placental physiology has gained growing interest, due to its crucial role in intrauterine development, with considerable long-term health consequences. This review discusses the evidence for nitric oxide (NO) as a critical player of placental development and function, with a special focus on endothelial nitric oxide synthase (eNOS) vascular effects. Also, the regulation of eNOS-dependent vascular responses in normal pregnancy and pregnancy-related diseases and their impact on prenatal and postnatal vascular health are discussed. Recent and compelling evidence has reinforced that eNOS regulation results from a complex network of processes, with novel data concerning mechanisms such as mechano-sensing, epigenetic, posttranslational modifications, and the expression of NO- and l-arginine-related pathways. In this regard, most of these mechanisms are expressed in an arterial-venous-specific manner and reflect traits of the fetal systemic circulation. Several studies using umbilical endothelial cells are not aimed to understand placental function but general endothelial function, reinforcing the influence of the placenta on general knowledge in physiology.
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Affiliation(s)
- Bernardo J Krause
- Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile
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10
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Rodríguez M, Valez V, Cimarra C, Blasina F, Radi R. Hypoxic-Ischemic Encephalopathy and Mitochondrial Dysfunction: Facts, Unknowns, and Challenges. Antioxid Redox Signal 2020; 33:247-262. [PMID: 32295425 DOI: 10.1089/ars.2020.8093] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Significance: Hypoxic-ischemic events due to intrapartum complications represent the second cause of neonatal mortality and initiate an acute brain disorder known as hypoxic-ischemic encephalopathy (HIE). In HIE, the brain undergoes primary and secondary energy failure phases separated by a latent phase in which partial neuronal recovery is observed. A hypoxic-ischemic event leads to oxygen restriction causing ATP depletion, neuronal oxidative stress, and cell death. Mitochondrial dysfunction and enhanced oxidant formation in brain cells are characteristic phenomena associated with energy failure. Recent Advances: Mitochondrial sources of oxidants in neurons include complex I of the mitochondrial respiratory chain, as a key contributor to O2•- production via succinate by a reverse electron transport mechanism. The reaction of O2•- with nitric oxide (•NO) yields peroxynitrite, a mitochondrial and cellular toxin. Quantitation of the redox state of cytochrome c oxidase, through broadband near-infrared spectroscopy, represents a promising monitoring approach to evaluate mitochondrial dysfunction in vivo in humans, in conjunction with the determination of cerebral oxygenation and their correlation with the severity of brain injury. Critical Issues: The energetic failure being a key phenomenon in HIE connected with the severity of the encephalopathy, measurement of mitochondrial dysfunction in vivo provides an approach to assess evolution, prognosis, and adequate therapies. Restoration of mitochondrial redox homeostasis constitutes a key therapeutic goal. Future Directions: While hypothermia is the only currently accepted therapy in clinical management to preserve mitochondrial function, other mitochondria-targeted and/or redox-based treatments are likely to synergize to ensure further efficacy.
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Affiliation(s)
- Marianela Rodríguez
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO) and Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay.,Departamento de Neonatología, Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
| | - Valeria Valez
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO) and Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
| | - Carolina Cimarra
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO) and Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
| | - Fernanda Blasina
- Departamento de Neonatología, Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
| | - Rafael Radi
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO) and Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
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Mahmoud AR, Kamel EO, Ahmed MA, Ahmed EA, Abd-Elhamid TH. Alleviation of Simvastatin-Induced Myopathy in Rats by the Standardized Extract of Ginkgo Biloba (EGb761): Insights into the Mechanisms of Action. Cells Tissues Organs 2020; 208:158-176. [PMID: 32369804 DOI: 10.1159/000507048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 03/07/2020] [Indexed: 01/24/2023] Open
Abstract
Statins are the most widely prescribed cholesterol-lowering drugs to reduce the risk of cardiovascular diseases. Statin-induced myopathy is the major side effect of this class of drugs. Here, we studied whether standardized leaf extracts of ginkgo biloba (EGb761) would improve simvastatin (SIM)-induced muscle changes. Sixty Wistar rats were allotted into six groups: control group, vehicle group receiving 0.5% carboxymethyl cellulose (CMC) for 30 days, SIM group receiving 80 mg/kg/day SIM in 0.5% CMC orally for 30 days, SIM withdrawal group treated with SIM for 16 days and sacrificed 14 days later, and EGb761-100 and EGb761-200 groups posttreated with either 100 or 200 mg/kg/day EGb761 orally. Muscle performance on the rotarod, serum creatine kinase (CK), coenzyme Q10 (CoQ10), serum and muscle nitrite, muscle malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) activities were estimated. Additionally, muscle samples were processed for histopathological evaluation. We found that SIM decreased muscle performance on the rotarod, serum CoQ10, as well as muscle SOD and CAT activities while it increased serum CK, serum and muscle nitrite, as well as muscle MDA levels. SIM also induced sarcoplasmic vacuolation, splitting of myofibers, disorganization of sarcomeres, and disintegration of myofilaments. In contrast, posttreatment with EGb761 increased muscle performance, serum CoQ10, as well as muscle SOD and CAT activities while it reduced serum CK as well as serum and muscle nitrite levels in a dose-dependent manner. Additionally, EGb761 reversed SIM-induced histopathological changes with better results obtained by its higher dose. Interestingly, SIM withdrawal increased muscle performance on the rotarod, reduce serum CK and CoQ10, and reduced serum and muscle nitrite while it reversed SIM-induced histopathological changes. However, SIM withdrawal was not effective enough to restore their normal values. Additionally, SIM withdrawal did not improve SIM-induce muscle MDA, SOD, or CAT activities during the period studied. Our results suggest that EGb761 posttreatment reversed SIM-induces muscle changes possibly through its antioxidant effects, elevation of CoQ10 levels, and antagonizing mitochondrial damage.
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Affiliation(s)
- Amany R Mahmoud
- Department of Human Anatomy and Embryology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Anatomy Unit, Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia
| | - Esam Omar Kamel
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
| | - Marwa A Ahmed
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Esraa A Ahmed
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Centre of Excellence in Environmental Studies, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Tarek Hamdy Abd-Elhamid
- Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt,
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Laranjinha J, Nunes C, Ledo A, Lourenço C, Rocha B, Barbosa RM. The Peculiar Facets of Nitric Oxide as a Cellular Messenger: From Disease-Associated Signaling to the Regulation of Brain Bioenergetics and Neurovascular Coupling. Neurochem Res 2020; 46:64-76. [PMID: 32193753 DOI: 10.1007/s11064-020-03015-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 03/07/2020] [Accepted: 03/12/2020] [Indexed: 12/13/2022]
Abstract
In this review, we address the regulatory and toxic role of ·NO along several pathways, from the gut to the brain. Initially, we address the role on ·NO in the regulation of mitochondrial respiration with emphasis on the possible contribution to Parkinson's disease via mechanisms that involve its interaction with a major dopamine metabolite, DOPAC. In parallel with initial discoveries of the inhibition of mitochondrial respiration by ·NO, it became clear the potential for toxic ·NO-mediated mechanisms involving the production of more reactive species and the post-translational modification of mitochondrial proteins. Accordingly, we have proposed a novel mechanism potentially leading to dopaminergic cell death, providing evidence that NO synergistically interact with DOPAC in promoting cell death via mechanisms that involve GSH depletion. The modulatory role of NO will be then briefly discussed as a master regulator on brain energy metabolism. The energy metabolism in the brain is central to the understanding of brain function and disease. The core role of ·NO in the regulation of brain metabolism and vascular responses is further substantiated by discussing its role as a mediator of neurovascular coupling, the increase in local microvessels blood flow in response to spatially restricted increase of neuronal activity. The many facets of NO as intracellular and intercellular messenger, conveying information associated with its spatial and temporal concentration dynamics, involve not only the discussion of its reactions and potential targets on a defined biological environment but also the regulation of its synthesis by the family of nitric oxide synthases. More recently, a novel pathway, out of control of NOS, has been the subject of a great deal of controversy, the nitrate:nitrite:NO pathway, adding new perspectives to ·NO biology. Thus, finally, this novel pathway will be addressed in connection with nitrate consumption in the diet and the beneficial effects of protein nitration by reactive nitrogen species.
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Affiliation(s)
- João Laranjinha
- Faculty of Pharmacy, University of Coimbra, Azinhaga Sta. Comba, 3000-548, Coimbra, Portugal. .,Center for Neuroscience and Cell Biology, University of Coimbra, Pólo 1, 3000-504, Coimbra, Portugal.
| | - Carla Nunes
- Faculty of Pharmacy, University of Coimbra, Azinhaga Sta. Comba, 3000-548, Coimbra, Portugal.,Center for Neuroscience and Cell Biology, University of Coimbra, Pólo 1, 3000-504, Coimbra, Portugal
| | - Ana Ledo
- Center for Neuroscience and Cell Biology, University of Coimbra, Pólo 1, 3000-504, Coimbra, Portugal
| | - Cátia Lourenço
- Center for Neuroscience and Cell Biology, University of Coimbra, Pólo 1, 3000-504, Coimbra, Portugal
| | - Bárbara Rocha
- Faculty of Pharmacy, University of Coimbra, Azinhaga Sta. Comba, 3000-548, Coimbra, Portugal.,Center for Neuroscience and Cell Biology, University of Coimbra, Pólo 1, 3000-504, Coimbra, Portugal
| | - Rui M Barbosa
- Faculty of Pharmacy, University of Coimbra, Azinhaga Sta. Comba, 3000-548, Coimbra, Portugal.,Center for Neuroscience and Cell Biology, University of Coimbra, Pólo 1, 3000-504, Coimbra, Portugal
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Gonzalez AM, Trexler ET. Effects of Citrulline Supplementation on Exercise Performance in Humans: A Review of the Current Literature. J Strength Cond Res 2020; 34:1480-1495. [DOI: 10.1519/jsc.0000000000003426] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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14
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Somasundaram V, Basudhar D, Bharadwaj G, No JH, Ridnour LA, Cheng RY, Fujita M, Thomas DD, Anderson SK, McVicar DW, Wink DA. Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism. Antioxid Redox Signal 2019; 30:1124-1143. [PMID: 29634348 PMCID: PMC6354612 DOI: 10.1089/ars.2018.7527] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 03/08/2018] [Indexed: 01/03/2023]
Abstract
SIGNIFICANCE Cancer is a complex disease, which not only involves the tumor but its microenvironment comprising different immune cells as well. Nitric oxide (NO) plays specific roles within tumor cells and the microenvironment and determines the rate of cancer progression, therapy efficacy, and patient prognosis. Recent Advances: Key understanding of the processes leading to dysregulated NO flux within the tumor microenvironment over the past decade has provided better understanding of the dichotomous role of NO in cancer and its importance in shaping the immune landscape. It is becoming increasingly evident that nitric oxide synthase 2 (NOS2)-mediated NO/reactive nitrogen oxide species (RNS) are heavily involved in cancer progression and metastasis in different types of tumor. More recent studies have found that NO from NOS2+ macrophages is required for cancer immunotherapy to be effective. CRITICAL ISSUES NO/RNS, unlike other molecules, are unique in their ability to target a plethora of oncogenic pathways during cancer progression. In this review, we subcategorize the different levels of NO produced by cells and shed light on the context-dependent temporal effects on cancer signaling and metabolic shift in the tumor microenvironment. FUTURE DIRECTIONS Understanding the source of NO and its spaciotemporal profile within the tumor microenvironment could help improve efficacy of cancer immunotherapies by improving tumor infiltration of immune cells for better tumor clearance.
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Affiliation(s)
- Veena Somasundaram
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - Debashree Basudhar
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - Gaurav Bharadwaj
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - Jae Hong No
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seoul, Republic of Korea
| | - Lisa A. Ridnour
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - Robert Y.S. Cheng
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - Mayumi Fujita
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
- Department of Basic Medical Sciences for Radiation Damages, National Institutes of Quantum and Radiological Science and Technology, Chiba, Japan
| | - Douglas D. Thomas
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois
| | - Stephen K. Anderson
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - Daniel W. McVicar
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - David A. Wink
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
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Vercesi AE, Castilho RF, Kowaltowski AJ, de Oliveira HCF, de Souza-Pinto NC, Figueira TR, Busanello ENB. Mitochondrial calcium transport and the redox nature of the calcium-induced membrane permeability transition. Free Radic Biol Med 2018; 129:1-24. [PMID: 30172747 DOI: 10.1016/j.freeradbiomed.2018.08.034] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/16/2018] [Accepted: 08/28/2018] [Indexed: 12/16/2022]
Abstract
Mitochondria possess a Ca2+ transport system composed of separate Ca2+ influx and efflux pathways. Intramitochondrial Ca2+ concentrations regulate oxidative phosphorylation, required for cell function and survival, and mitochondrial redox balance, that participates in a myriad of signaling and damaging pathways. The interaction between Ca2+ accumulation and redox imbalance regulates opening and closing of a highly regulated inner membrane pore, the membrane permeability transition pore (PTP). In this review, we discuss the regulation of the PTP by mitochondrial oxidants, reactive nitrogen species, and the interactions between these species and other PTP inducers. In addition, we discuss the involvement of mitochondrial redox imbalance and PTP in metabolic conditions such as atherogenesis, diabetes, obesity and in mtDNA stability.
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Affiliation(s)
- Anibal E Vercesi
- Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil.
| | - Roger F Castilho
- Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Alicia J Kowaltowski
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Helena C F de Oliveira
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, Universidade Estadual de Campinas, SP, Brazil
| | - Nadja C de Souza-Pinto
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Tiago R Figueira
- Escola de Educação Física e Esporte de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
| | - Estela N B Busanello
- Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil
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16
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Lourenço CF, Ledo A, Caetano M, Barbosa RM, Laranjinha J. Age-Dependent Impairment of Neurovascular and Neurometabolic Coupling in the Hippocampus. Front Physiol 2018; 9:913. [PMID: 30065657 PMCID: PMC6056650 DOI: 10.3389/fphys.2018.00913] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 06/21/2018] [Indexed: 11/24/2022] Open
Abstract
Neurovascular and neurometabolic coupling are critical and complex processes underlying brain function. Perturbations in the regulation of these processes are, likely, early dysfunctional alterations in pathological brain aging and age-related neurodegeneration. Evidences support the role of nitric oxide (•NO) as a key messenger both in neurovascular coupling, by signaling from neurons to blood vessels, and in neurometabolic coupling, by modulating O2 utilization by mitochondria. In the present study, we investigated the functionality of neurovascular and neurometabolic coupling in connection to •NO signaling and in association to cognitive performance during aging. For this, we performed in vivo simultaneous measurements of •NO, O2 and cerebral blood flow (CBF) in the hippocampus of F344 rats along chronological age in response to glutamatergic activation and in correlation with cognitive performance. Firstly, it is evidenced the temporal sequence of events upon glutamate stimulation of hippocampal dentate gyrus, encompassing the local and transitory increase of •NO followed by transitory local changes of CBF and pO2. Specifically, the transient increase of •NO is followed by an increase of CBF and biphasic changes of the local pO2. We observed that, although the glutamate-induced •NO dynamics were not significantly affected by aging, the correspondent hemodynamic was progressively diminished accompanying a decline in learning and memory. Noteworthy, in spite of a compromised blood supply, in aged rats we observed an increased ΔpO2 associated to the hemodynamic response, suggestive of a decrease in the global metabolic rate of O2. Furthermore, the impairment in the neurovascular coupling observed along aging in F344 rats was mimicked in young rats by promoting an unbalance in redox status toward oxidation via intracellular generation of superoxide radical. This observation strengthens the idea that oxidative stress may have a critical role in the neurovascular uncoupling underlying brain aging and dysfunction. Overall, data supports an impairment of neurovascular response in connection with cognition decline due to oxidative environment-dependent compromised •NO signaling from neurons to vessels during aging.
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Affiliation(s)
- Cátia F Lourenço
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Ana Ledo
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Miguel Caetano
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Rui M Barbosa
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - João Laranjinha
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
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17
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Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6290931. [PMID: 30050658 PMCID: PMC6040266 DOI: 10.1155/2018/6290931] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 03/13/2018] [Indexed: 01/06/2023]
Abstract
Hydrogen sulfide (H2S) has emerged as a relevant signaling molecule in physiology, taking its seat as a bona fide gasotransmitter akin to nitric oxide (NO) and carbon monoxide (CO). After being merely regarded as a toxic poisonous molecule, it is now recognized that mammalian cells are equipped with sophisticated enzymatic systems for H2S production and breakdown. The signaling role of H2S is mainly related to its ability to modify different protein targets, particularly by promoting persulfidation of protein cysteine residues and by interacting with metal centers, mostly hemes. H2S has been shown to regulate a myriad of cellular processes with multiple physiological consequences. As such, dysfunctional H2S metabolism is increasingly implicated in different pathologies, from cardiovascular and neurodegenerative diseases to cancer. As a highly diffusible reactive species, the intra- and extracellular levels of H2S have to be kept under tight control and, accordingly, regulation of H2S metabolism occurs at different levels. Interestingly, even though H2S, NO, and CO have similar modes of action and parallel regulatory targets or precisely because of that, there is increasing evidence of a crosstalk between the three gasotransmitters. Herein are reviewed the biochemistry, metabolism, and signaling function of hydrogen sulfide, as well as its interplay with the other gasotransmitters, NO and CO.
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18
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Al-Dashti YA, Holt RR, Stebbins CL, Keen CL, Hackman RM. Dietary Flavanols: A Review of Select Effects on Vascular Function, Blood Pressure, and Exercise Performance. J Am Coll Nutr 2018; 37:553-567. [PMID: 29718795 DOI: 10.1080/07315724.2018.1451788] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
An individual's diet affects numerous physiological functions and can play an important role in reducing the risk of cardiovascular disease. Epidemiological and clinical studies suggest that dietary flavanols can be an important modulator of vascular risk. Diets and plant extracts rich in flavanols have been reported to lower blood pressure, especially in prehypertensive and hypertensive individuals. Flavanols may act in part through signaling pathways that affect vascular function, nitric oxide availability, and the release of endothelial-derived relaxing and constricting factors. During exercise, flavanols have been reported to modulate metabolism and respiration (e.g., maximal oxygen uptake, O2 cost of exercise, and energy expenditure), and reduce oxidative stress and inflammation, resulting in increased skeletal muscle efficiency and endurance capacity. Flavanol-induced reductions in blood pressure during exercise may decrease the work of the heart. Collectively, these effects suggest that flavanols can act as an ergogenic aid to help delay the onset of fatigue. More research is needed to better clarify the effects of flavanols on vascular function, blood pressure regulation, and exercise performance and establish safe and effective levels of intake. Flavanol-rich foods and food products can be useful components of a healthy diet and lifestyle program for those seeking to better control their blood pressure or to enhance their physical activity. Key teaching points • Epidemiological and clinical studies indicate that dietary flavanols can reduce the risk of vascular disease. • Diets and plant extracts rich in flavanols have been reported to lower blood pressure and improve exercise performance in humans. • Mechanisms by which flavanols may reduce blood pressure function include alterations in signaling pathways that affect vascular function, nitric oxide availability, and the release of endothelial-derived relaxation and constriction factors. • Mechanisms by which flavanols may enhance exercise performance include modulation of metabolism and respiration (e.g., maximal oxygen uptake, O2 cost of exercise, and energy expenditure) and reduction of oxidative stress and inflammation. These effects can result in increased skeletal muscle efficiency and endurance capacity. • Further research is needed to clarify the amount, timing, and frequency of flavanol intake for blood pressure regulation and exercise performance.
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Affiliation(s)
- Yousef A Al-Dashti
- a Department of Nutrition , University of California, Davis , Davis , California , USA
| | - Roberta R Holt
- a Department of Nutrition , University of California, Davis , Davis , California , USA
| | - Charles L Stebbins
- b Department of Internal Medicine , University of California, Davis , Davis , California , USA
| | - Carl L Keen
- a Department of Nutrition , University of California, Davis , Davis , California , USA.,b Department of Internal Medicine , University of California, Davis , Davis , California , USA
| | - Robert M Hackman
- a Department of Nutrition , University of California, Davis , Davis , California , USA
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19
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Increasing vegetable intake to obtain the health promoting and ergogenic effects of dietary nitrate. Eur J Clin Nutr 2018; 72:1485-1489. [PMID: 29559721 DOI: 10.1038/s41430-018-0140-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 12/06/2017] [Accepted: 02/14/2018] [Indexed: 11/08/2022]
Abstract
Increased consumption of dietary nitrate increases plasma nitrate and nitrite concentrations, and has been shown to elicit cardio-protective effects and improve exercise performance. Nitrate consumption in the habitual diet is mainly dependent on nitrate-rich vegetables, such as green leafy and root vegetables, with total vegetable consumption accounting for approximately 50-85% of our daily nitrate intake. Whereas 'supplementation' with dietary nitrate in research studies has mainly been accomplished through the use of (concentrated) nitrate-rich beetroot juice, dietary strategies focusing on increased intake of nitrate-rich vegetables may represent a similarly effective alternative for increasing dietary nitrate intake and, as such, obtaining the associated cardiovascular health and ergogenic benefits.
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20
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Lee SR, Nilius B, Han J. Gaseous Signaling Molecules in Cardiovascular Function: From Mechanisms to Clinical Translation. Rev Physiol Biochem Pharmacol 2018; 174:81-156. [PMID: 29372329 DOI: 10.1007/112_2017_7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Carbon monoxide (CO), hydrogen sulfide (H2S), and nitric oxide (NO) constitute endogenous gaseous molecules produced by specific enzymes. These gases are chemically simple, but exert multiple effects and act through shared molecular targets to control both physiology and pathophysiology in the cardiovascular system (CVS). The gases act via direct and/or indirect interactions with each other in proteins such as heme-containing enzymes, the mitochondrial respiratory complex, and ion channels, among others. Studies of the major impacts of CO, H2S, and NO on the CVS have revealed their involvement in controlling blood pressure and in reducing cardiac reperfusion injuries, although their functional roles are not limited to these conditions. In this review, the basic aspects of CO, H2S, and NO, including their production and effects on enzymes, mitochondrial respiration and biogenesis, and ion channels are briefly addressed to provide insight into their biology with respect to the CVS. Finally, potential therapeutic applications of CO, H2S, and NO with the CVS are addressed, based on the use of exogenous donors and different types of delivery systems.
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Affiliation(s)
- Sung Ryul Lee
- Department of Convergence Biomedical Science, Cardiovascular and Metabolic Disease Center, College of Medicine, Inje University, Busan, Republic of Korea
| | - Bernd Nilius
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Jin Han
- National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea.
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21
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Singer M. Critical illness and flat batteries. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2017; 21:309. [PMID: 29297363 PMCID: PMC5751585 DOI: 10.1186/s13054-017-1913-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
An exaggerated, dysregulated host response to insults such as infection (i.e. sepsis), trauma and ischaemia-reperfusion injury can result in multiple organ dysfunction and death. While the focus of research in this area has largely centred on inflammation and immunity, a crucial missing link is the precise identification of mechanisms at the organ level that cause this physiological-biochemical failure. Any hypothesis must reconcile this functional organ failure with minimal signs of cell death, availability of oxygen, and (often) minimal early local inflammatory cell infiltrate. These failed organs also retain the capacity to usually recover, even those that are poorly regenerative. A metabolic-bioenergetic shutdown, akin to hibernation or aestivation, is the most plausible explanation currently advanced. This shutdown appears driven by a perfect storm of compromised mitochondrial oxidative phosphorylation related to inhibition by excessive inflammatory mediators, direct oxidant stress, a tissue oxygen deficit in the unresuscitated phase, altered hormonal drive, and downregulation of genes encoding mitochondrial proteins. In addition, the efficiency of oxidative phosphorylation may be affected by a substrate shift towards fat metabolism and increased uncoupling. A lack of sufficient ATP provision to fuel normal metabolic processes will drive downregulation of metabolism, and thus cellular functionality. In turn, a decrease in metabolism will provide negative feedback to the mitochondrion, inducing a bioenergetic shutdown. Arguably, these processes may offer protection against a prolonged inflammatory hit by sparing the cell from initiation of death pathways, thereby explaining the lack of significant morphological change. A narrow line may exist between adaptation and maladaptation. This places a considerable challenge on any therapeutic modulation to provide benefit rather than harm.
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Affiliation(s)
- Mervyn Singer
- Bloomsbury Institute of Intensive Care Medicine, Cruciform Building, University College London, London, WC1E 6BT, UK.
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22
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Place TL, Domann FE, Case AJ. Limitations of oxygen delivery to cells in culture: An underappreciated problem in basic and translational research. Free Radic Biol Med 2017; 113:311-322. [PMID: 29032224 PMCID: PMC5699948 DOI: 10.1016/j.freeradbiomed.2017.10.003] [Citation(s) in RCA: 266] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 10/02/2017] [Accepted: 10/04/2017] [Indexed: 01/08/2023]
Abstract
Molecular oxygen is one of the most important variables in modern cell culture systems. Fluctuations in its concentration can affect cell growth, differentiation, signaling, and free radical production. In order to maintain culture viability, experimental validity, and reproducibility, it is imperative that oxygen levels be consistently maintained within physiological "normoxic" limits. Use of the term normoxia, however, is not consistent among scientists who experiment in cell culture. It is typically used to describe the atmospheric conditions of a standard incubator, not the true microenvironment to which the cells are exposed. This error may lead to the situation where cells grown in a standard "normoxic" oxygen concentration may actually be experiencing a wide range of conditions ranging from hyperoxia to near-anoxic conditions at the cellular level. This apparent paradox is created by oxygen's sluggish rate of diffusion through aqueous medium, and the generally underappreciated effects that cell density, media volume, and barometric pressure can have on pericellular oxygen concentration in a cell culture system. This review aims to provide an overview of this phenomenon we have termed "consumptive oxygen depletion" (COD), and includes a basic review of the physics, potential consequences, and alternative culture methods currently available to help circumvent this largely unrecognized problem.
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Affiliation(s)
- Trenton L. Place
- Department of Obstetrics & Gynecology, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Frederick E. Domann
- Department of Radiation Oncology, Carver College of Medicine, The University of Iowa, Iowa City, IA
- Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IA
- Department of Surgery, Carver College of Medicine, The University of Iowa, Iowa City, IA
- Corresponding authors: Department of Physiology, University of Nebraska Medical Center, Omaha, NE 68198.
| | - Adam J. Case
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE
- Corresponding authors: Department of Physiology, University of Nebraska Medical Center, Omaha, NE 68198.
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23
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Tengan CH, Moraes CT. NO control of mitochondrial function in normal and transformed cells. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2017; 1858:573-581. [PMID: 28216426 PMCID: PMC5487294 DOI: 10.1016/j.bbabio.2017.02.009] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 01/19/2017] [Accepted: 02/15/2017] [Indexed: 10/25/2022]
Abstract
Nitric oxide (NO) is a signaling molecule with multiple facets and involved in numerous pathological process, including cancer. Among the different pathways where NO has a functionally relevant participation, is the control of mitochondrial respiration and biogenesis. NO is able to inhibit the electron transport chain, mainly at Complex IV, regulating oxygen consumption and ATP generation, but at the same time, can also induce increase in reactive oxygen and nitrogen species. The presence of reactive species can induce oxidative damage or participate in redox signaling. In this review, we discuss how NO affects mitochondrial respiration and mitochondrial biogenesis, and how it influences the development of mitochondrial deficiency and cancer. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
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Affiliation(s)
- Celia H Tengan
- Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Universidade Federal de São Paulo, R. Pedro de Toledo, 781, setimo andar, frente, 04039-032, São Paulo, SP, Brazil.
| | - Carlos T Moraes
- University of Miami Miller School of Medicine, Dept. of Neurology and Cell Biology, 1420 NW 9th Avenue, Rm.229, Miami, FL 33136, USA.
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24
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Lourenço CF, Ledo A, Barbosa RM, Laranjinha J. Neurovascular-neuroenergetic coupling axis in the brain: master regulation by nitric oxide and consequences in aging and neurodegeneration. Free Radic Biol Med 2017; 108:668-682. [PMID: 28435052 DOI: 10.1016/j.freeradbiomed.2017.04.026] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 02/21/2017] [Accepted: 04/18/2017] [Indexed: 02/08/2023]
Abstract
The strict energetic demands of the brain require that nutrient supply and usage be fine-tuned in accordance with the specific temporal and spatial patterns of ever-changing levels of neuronal activity. This is achieved by adjusting local cerebral blood flow (CBF) as a function of activity level - neurovascular coupling - and by changing how energy substrates are metabolized and shuttled amongst astrocytes and neurons - neuroenergetic coupling. Both activity-dependent increase of CBF and O2 and glucose utilization by active neural cells are inextricably linked, establishing a functional metabolic axis in the brain, the neurovascular-neuroenergetic coupling axis. This axis incorporates and links previously independent processes that need to be coordinated in the normal brain. We here review evidence supporting the role of neuronal-derived nitric oxide (•NO) as the master regulator of this axis. Nitric oxide is produced in tight association with glutamatergic activation and, diffusing several cell diameters, may interact with different molecular targets within each cell type. Hemeproteins such as soluble guanylate cyclase, cytochrome c oxidase and hemoglobin, with which •NO reacts at relatively fast rates, are but a few of the key in determinants of the regulatory role of •NO in the neurovascular-neuroenergetic coupling axis. Accordingly, critical literature supporting this concept is discussed. Moreover, in view of the controversy regarding the regulation of catabolism of different neural cells, we further discuss key aspects of the pathways through which •NO specifically up-regulates glycolysis in astrocytes, supporting lactate shuttling to neurons for oxidative breakdown. From a biomedical viewpoint, derailment of neurovascular-neuroenergetic axis is precociously linked to aberrant brain aging, cognitive impairment and neurodegeneration. Thus, we summarize current knowledge of how both neurovascular and neuroenergetic coupling are compromised in aging, traumatic brain injury, epilepsy and age-associated neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, suggesting that a shift in cellular redox balance may contribute to divert •NO bioactivity from regulation to dysfunction.
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Affiliation(s)
- Cátia F Lourenço
- Center for Neuroscience and Cell Biology, University of Coimbra, Portugal
| | - Ana Ledo
- Center for Neuroscience and Cell Biology, University of Coimbra, Portugal
| | - Rui M Barbosa
- Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - João Laranjinha
- Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
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25
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Truse R, Hinterberg J, Schulz J, Herminghaus A, Weber A, Mettler-Altmann T, Bauer I, Picker O, Vollmer C. Effect of Topical Iloprost and Nitroglycerin on Gastric Microcirculation and Barrier Function during Hemorrhagic Shock in Dogs. J Vasc Res 2017; 54:109-121. [PMID: 28441653 DOI: 10.1159/000464262] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 02/18/2017] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Topical drug application is used to avoid systemic side effects. The aim of this study was to analyze whether locally applied iloprost or nitroglycerin influence gastric mucosal perfusion, oxygenation, and barrier function during physiological and hemorrhagic conditions. METHODS In repeated experiments, 5 anesthetized dogs received iloprost, nitroglycerin, or normal saline during physiological and hemorrhagic (-20% blood volume) conditions. Macro- and microcirculatory variables were recorded continuously. Gastric barrier function was assessed via translocation of sucrose into the blood. RESULTS During hemorrhage, gastric mucosal oxygenation decreased from 77 ± 4 to 37 ± 7%. This effect was attenuated by nitroglycerin (78 ± 6 to 47 ± 13%) and iloprost (82 ± 4 to 54 ± 9%). Sucrose plasma levels increased during hemorrhage from 7 ± 4 to 55 ± 15 relative amounts. This was alleviated by nitroglycerin (5 ± 8 to 29 ± 38 relative amounts). These effects were independent of systemic hemodynamic variables. CONCLUSIONS During hemorrhage, topical nitroglycerin and iloprost improve regional gastric oxygenation without affecting perfusion. Nitroglycerin attenuated the shock-induced impairment of the mucosal barrier integrity. Thus, local drug application improves gastric microcirculation without compromising systemic hemodynamic variables, and it may also protect mucosal barrier function.
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Affiliation(s)
- Richard Truse
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
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26
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Caballano-Infantes E, Terron-Bautista J, Beltrán-Povea A, Cahuana GM, Soria B, Nabil H, Bedoya FJ, Tejedo JR. Regulation of mitochondrial function and endoplasmic reticulum stress by nitric oxide in pluripotent stem cells. World J Stem Cells 2017; 9:26-36. [PMID: 28289506 PMCID: PMC5329687 DOI: 10.4252/wjsc.v9.i2.26] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 09/09/2016] [Accepted: 01/14/2017] [Indexed: 02/06/2023] Open
Abstract
Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide (NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca2+ flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstrated the need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.
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Gerber L, Madsen SS, Jensen FB. Cortisol regulates nitric oxide synthase in freshwater and seawater acclimated rainbow trout, Oncorhynchus mykiss. Comp Biochem Physiol A Mol Integr Physiol 2016; 204:1-8. [PMID: 27838356 DOI: 10.1016/j.cbpa.2016.11.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 11/02/2016] [Accepted: 11/07/2016] [Indexed: 12/16/2022]
Abstract
Cortisol and nitric oxide (NO) are regulators of ion transport and metabolic functions in fish. In the gill, they show opposite effects on Na+/K+-ATPase (NKA) activity: cortisol stimulates NKA activity while NO inhibits NKA activity. We hypothesized that cortisol may impact NO production in osmoregulatory tissues by regulating NO synthase (NOS) expression. We evaluated the influence of cortisol treatment on mRNA expression of Nos1 and Nos2 in gill, kidney and middle intestine of both freshwater (FW) and seawater (SW) acclimated rainbow trout and found both tissue- and salinity-dependent effects. Nos2 expression was down-regulated in the gill by cortisol injection in both FW and SW trout. This was substantiated by incubating gill tissue with cortisol ex vivo. Similarly, cortisol injection significantly down-regulated Nos2 expression in kidney of SW fish but not in FW fish. In the middle intestine, Nos2 expression was up-regulated by cortisol injection in FW but unchanged in SW fish. Nos1 expression was up-regulated by cortisol injection in FW kidney and down-regulated in SW kidney, whereas it was unaffected in gill and middle intestine of FW and SW fish. Our data provide the first evidence that cortisol may influence NO production in fish by regulating Nos expression. Indeed, the down-regulation of Nos2 expression by cortisol in the gill may prevent the inhibitory effect of NO on NKA activity thereby furthering the stimulatory effect of cortisol on ion-transport.
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Affiliation(s)
- Lucie Gerber
- Department of Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
| | - Steffen S Madsen
- Department of Biology, University of Southern Denmark, DK-5230 Odense M, Denmark
| | - Frank B Jensen
- Department of Biology, University of Southern Denmark, DK-5230 Odense M, Denmark
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Wende AR, Young ME, Chatham J, Zhang J, Rajasekaran NS, Darley-Usmar VM. Redox biology and the interface between bioenergetics, autophagy and circadian control of metabolism. Free Radic Biol Med 2016; 100:94-107. [PMID: 27242268 PMCID: PMC5124549 DOI: 10.1016/j.freeradbiomed.2016.05.022] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 05/25/2016] [Accepted: 05/26/2016] [Indexed: 12/01/2022]
Abstract
Understanding molecular mechanisms that underlie the recent emergence of metabolic diseases such as diabetes and heart failure has revealed the need for a multi-disciplinary research integrating the key metabolic pathways which change the susceptibility to environmental or pathologic stress. At the physiological level these include the circadian control of metabolism which aligns metabolism with temporal demand. The mitochondria play an important role in integrating the redox signals and metabolic flux in response to the changing activities associated with chronobiology, exercise and diet. At the molecular level this involves dynamic post-translational modifications regulating transcription, metabolism and autophagy. In this review we will discuss different examples of mechanisms which link these processes together. An important pathway capable of linking signaling to metabolism is the post-translational modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc). This is a nutrient regulated protein modification that plays an important role in impaired cellular stress responses. Circadian clocks have also emerged as critical regulators of numerous cardiometabolic processes, including glucose/lipid homeostasis, hormone secretion, redox status and cardiovascular function. Central to these pathways are the response of autophagy, bioenergetics to oxidative stress, regulated by Keap1/Nrf2 and mechanisms of metabolic control. The extension of these ideas to the emerging concept of bioenergetic health will be discussed.
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Affiliation(s)
- Adam R Wende
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Martin E Young
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - John Chatham
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jianhua Zhang
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Namakkal S Rajasekaran
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Victor M Darley-Usmar
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; UAB Mitochondrial Medicine Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Pannala VR, Camara AKS, Dash RK. Modeling the detailed kinetics of mitochondrial cytochrome c oxidase: Catalytic mechanism and nitric oxide inhibition. J Appl Physiol (1985) 2016; 121:1196-1207. [PMID: 27633738 DOI: 10.1152/japplphysiol.00524.2016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 09/11/2016] [Indexed: 01/03/2023] Open
Abstract
Cytochrome c oxidase (CcO) catalyzes the exothermic reduction of O2 to H2O by using electrons from cytochrome c, and hence plays a crucial role in ATP production. Although details on the enzyme structure and redox centers involved in O2 reduction have been known, there still remains a considerable ambiguity on its mechanism of action, e.g., the number of sequential electrons donated to O2 in each catalytic step, the sites of protonation and proton pumping, and nitric oxide (NO) inhibition mechanism. In this work, we developed a thermodynamically constrained mechanistic mathematical model for the catalytic action of CcO based on available kinetic data. The model considers a minimal number of redox centers on CcO and couples electron transfer and proton pumping driven by proton motive force (PMF), and accounts for the inhibitory effects of NO on the reaction kinetics. The model is able to fit well all the available kinetic data under diverse experimental conditions with a physiologically realistic unique parameter set. The model predictions show that: 1) the apparent Km of O2 varies considerably and increases from fully reduced to fully oxidized cytochrome c depending on pH and the energy state of mitochondria, and 2) the intermediate enzyme states depend on pH and cytochrome c redox fraction and play a central role in coupling mitochondrial respiration to PMF. The developed CcO model can easily be integrated into existing mitochondrial bioenergetics models to understand the role of the enzyme in controlling oxidative phosphorylation in normal and disease conditions.
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Affiliation(s)
- Venkat R Pannala
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Amadou K S Camara
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ranjan K Dash
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; .,Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin; and
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Arun M, Balamuralikrishnan B, Kumar AK, Sureshkumar S, Mustaqahamed S, Mohanadevi S, Easwaran M, Raman N, Haripriya KB, Palanivel H, Balachandar V, Sasikala K. Association between exposure to nitric oxide and changes in select molecular markers of health among men in the gold jewelry manufacturing industry. KARBALA INTERNATIONAL JOURNAL OF MODERN SCIENCE 2016. [DOI: 10.1016/j.kijoms.2016.04.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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31
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Li Y, Cui X, Xu W, Ohanjanian L, Sampath-Kumar H, Suffredini D, Moayeri M, Leppla S, Fitz Y, Eichacker PQ. Nitric oxide production contributes to Bacillus anthracis edema toxin-associated arterial hypotension and lethality: ex vivo and in vivo studies in the rat. Am J Physiol Heart Circ Physiol 2016; 311:H781-93. [PMID: 27448553 DOI: 10.1152/ajpheart.00163.2016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 07/19/2016] [Indexed: 01/26/2023]
Abstract
We showed previously that Bacillus anthracis edema toxin (ET), comprised of protective antigen (PA) and edema factor (EF), inhibits phenylephrine (PE)-induced contraction in rat aortic rings and these effects are diminished in endothelial-denuded rings. Therefore, employing rat aortic ring and in vivo models, we tested the hypothesis that nitric oxide (NO) contributes to ET's arterial effects. Compared with rings challenged with PA alone, ET (PA + EF) reduced PE-stimulated maximal contractile force (MCF) and increased the PE concentration producing 50% MCF (EC50) (P < 0.0001). Compared with placebo, l-nitro-arginine methyl-ester (l-NAME), an NO synthase (NOS) inhibitor, reduced ET's effects on MCF and EC50 in patterns that approached or were significant (P = 0.06 and 0.03, respectively). In animals challenged with 24-h ET infusions, l-NAME (0.5 or 1.0 mg·kg(-1)·h(-1)) coadministration increased survival to 17 of 28 animals (60.7%) compared with 4 of 27 (14.8%) given placebo (P = 0.01). Animals receiving l-NAME but no ET all survived. Compared with PBS challenge, ET increased NO levels at 24 h and l-NAME decreased these increases (P < 0.0001). ET infusion decreased mean arterial blood pressure (MAP) in placebo and l-NAME-treated animals (P < 0.0001) but l-NAME reduced decreases in MAP with ET from 9 to 24 h (P = 0.03 for the time interaction). S-methyl-l-thiocitrulline, a selective neuronal NOS inhibitor, had effects in rings and, at a high dose in vivo models, comparable to l-NAME, whereas N'-[3-(aminomethyl)benzyl]-acetimidamide, a selective inducible NOS inhibitor, did not. NO production contributes to ET's arterial relaxant, hypotensive, and lethal effects in the rat.
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Affiliation(s)
- Yan Li
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and
| | - Xizhong Cui
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and
| | - Wanying Xu
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and
| | - Lernik Ohanjanian
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and
| | - Hanish Sampath-Kumar
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and
| | - Dante Suffredini
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and
| | - Mahtab Moayeri
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Stephen Leppla
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Yvonne Fitz
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and
| | - Peter Q Eichacker
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; and
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Subramanian D, Gupta S. Pharmacokinetic study of amaranth extract in healthy humans: A randomized trial. Nutrition 2016; 32:748-53. [DOI: 10.1016/j.nut.2015.12.041] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 12/28/2015] [Accepted: 12/28/2015] [Indexed: 02/05/2023]
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33
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Vicente JB, Malagrinò F, Arese M, Forte E, Sarti P, Giuffrè A. Bioenergetic relevance of hydrogen sulfide and the interplay between gasotransmitters at human cystathionine β-synthase. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2016; 1857:1127-1138. [PMID: 27039165 DOI: 10.1016/j.bbabio.2016.03.030] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 03/07/2016] [Accepted: 03/28/2016] [Indexed: 12/27/2022]
Abstract
Merely considered as a toxic gas in the past, hydrogen sulfide (H2S) is currently viewed as the third 'gasotransmitter' in addition to nitric oxide (NO) and carbon monoxide (CO), playing a key signalling role in human (patho)physiology. H2S can either act as a substrate or, similarly to CO and NO, an inhibitor of mitochondrial respiration, in the latter case by targeting cytochrome c oxidase (CcOX). The impact of H(2)S on mitochondrial energy metabolism crucially depends on the bioavailability of this gaseous molecule and its interplay with the other two gasotransmitters. The H(2)S-producing human enzyme cystathionine β-synthase (CBS), sustaining cellular bioenergetics in colorectal cancer cells, plays a role in the interplay between gasotransmitters. The enzyme was indeed recently shown to be negatively modulated by physiological concentrations of CO and NO, particularly in the presence of its allosteric activator S-adenosyl-l-methionine (AdoMet). These newly discovered regulatory mechanisms are herein reviewed. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
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Affiliation(s)
- João B Vicente
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República (EAN), 2780-156 Oeiras, Portugal.
| | - Francesca Malagrinò
- Department of Biochemical Sciences and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Marzia Arese
- Department of Biochemical Sciences and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Elena Forte
- Department of Biochemical Sciences and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Paolo Sarti
- Department of Biochemical Sciences and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Alessandro Giuffrè
- CNR Institute of Molecular Biology and Pathology, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
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Buckler KJ, Turner PJ. Functional Properties of Mitochondria in the Type-1 Cell and Their Role in Oxygen Sensing. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 860:69-80. [PMID: 26303469 DOI: 10.1007/978-3-319-18440-1_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
The identity of the oxygen sensor in arterial chemoreceptors has been the subject of much speculation. One of the oldest hypotheses is that oxygen is sensed through oxidative phosphorylation. There is a wealth of data demonstrating that arterial chemoreceptors are excited by inhibitors of oxidative phosphorylation. These compounds mimic the effects of hypoxia inhibiting TASK1/3 potassium channels causing membrane depolarisation calcium influx and neurosecretion. The TASK channels of Type-I cells are also sensitive to cytosolic MgATP. The existence of a metabolic signalling pathway in Type-1 cells is thus established; the contentious issue is whether this pathway is also used for acute oxygen sensing. The main criticism is that because cytochrome oxidase has a high affinity for oxygen (P50 ≈ 0.2 mmHg) mitochondrial metabolism should be insensitive to physiological hypoxia. This argument is however predicated on the assumption that chemoreceptor mitochondria are analogous to those of other tissues. We have however obtained new evidence to support the hypothesis that type-1 cell mitochondria are not like those of other cells in that they have an unusually low affinity for oxygen (Mills E, Jobsis FF, J Neurophysiol 35(4):405-428, 1972; Duchen MR, Biscoe TJ, J Physiol 450:13-31, 1992a). Our data confirm that mitochondrial membrane potential, NADH, electron transport and cytochrome oxidase activity in the Type-1 cell are all highly sensitive to hypoxia. These observations not only provide exceptionally strong support for the metabolic hypothesis but also reveal an unknown side of mitochondrial behaviour.
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Affiliation(s)
- Keith J Buckler
- Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK,
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MAIONE D, CICERO AFG, BACCHELLI S, COSENTINO ER, DEGLI ESPOSTI D, MANNERS DN, RINALDI ER, ROSTICCI M, SENALDI R, AMBROSIONI E, BORGHI C. The VO2-on Kinetics in Constant Load Exercise Sub-Anaerobic Threshold Reflects Endothelial Function and Dysfunction in Muscle Microcirculation. Physiol Res 2015; 64:807-19. [DOI: 10.33549/physiolres.932833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
To propose a test to evaluate endothelial function, based on VO2 on-transition kinetics in sub-anaerobic threshold (AT) constant load exercise, we tested healthy subjects and patients with ischemic-hypertensive cardiopathy by two cardiopulmonary tests on a cycle ergometer endowed with an electric motor to overcome initial inertia: a pre-test and, after at least 24 h, one 6 min constant load exercise at 90 % AT. We measured net phase 3 VO2-on kinetics and, by phase 2 time constant (τ), valued endothelial dysfunction. We found shorter τ in repeated tests, shorter time between first and second test, by persisting endothelium-dependent arteriolar vasodilatation and/or several other mechanisms. Reducing load to 80 % and 90 % AT did not produce significant changes in τ of healthy volunteers, while in heart patients an AT load of 70 %, compared to 80 % AT, shortened τ (=4.38±1.65 s, p=0.013). In heart patients, no correlation was found between NYHA class, ejection fraction (EF), and the two variables derived from incremental cycle cardio-pulmonary exercise, as well as between EF and τ; while NYHA class groups were well correlated with τ duration (r=0.92, p=0.0001). Doxazosin and tadalafil also significantly reduced τ. In conclusion, the O2 consumption kinetics during the on-transition of constant load exercise below the anaerobic threshold are highly sensitive to endothelial function in muscular microcirculation, and constitute a marker for the evaluation of endothelial dysfunction.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - C. BORGHI
- Department of Medicine and Surgery Sciences, University of Bologna, Italy
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Zhang Y, Ye C, Wang A, Zhu X, Chen C, Xian J, Sun Z. Isolated and combined exposure to ammonia and nitrite in giant freshwater pawn (Macrobrachium rosenbergii): effects on the oxidative stress, antioxidant enzymatic activities and apoptosis in haemocytes. ECOTOXICOLOGY (LONDON, ENGLAND) 2015; 24:1601-1610. [PMID: 25967939 DOI: 10.1007/s10646-015-1477-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/29/2015] [Indexed: 06/04/2023]
Abstract
The residual contaminators such as ammonia and nitrite are widely considered as relevant sources of aquatic environmental pollutants, posing a great threat to shrimp survival. To study the toxicological effects of ammonia and nitrite exposure on the innate immune response in invertebrates, we investigated the oxidative stress and apoptosis in haemocytes of freshwater prawn (Macrobrachium rosenbergii) under isolated and combined exposure to ammonia and nitrite in order to provide useful information about adult prawn immune responses. M. rosenbergii (13.44 ± 2.75 g) were exposed to 0, 5, and 25 mg/L total ammonia-N (TAN) and 0, 5, and 20 mg/L nitrite-N for 24 h. All ammonia concentrations were combined with all nitrite concentrations, making a total of nine treatments studied. Following the exposure treatment, antioxidant enzyme activity, reactive oxygen species (ROS) generation, nitric oxide (NO) generation, and apoptotic cell ratio of haemocytes were measured using flow cytometry. Results indicated that ROS generation was sensitive to the combined effect of ammonia and nitrite, which subsequently affected the Cu-Zn SOD activity. In addition, CAT showed the highest activity at 5 mg/L TAN while GPx decreased at 5 mg/L TAN and returned towards baseline at 25 mg/L. NO generation synchronized with the apoptotic cell ratio in haemocytes, indicating that NO production was closely associated with programmed cell death. Both NO production and apoptotic ratios significantly decreased following 25 mg/L TAN, which may be due to the antagonistic regulation of NO and GPx. We hypothesized that the toxicological effect of nitrite exhibited less change in physiological changes compared to that of ammonia, because of the high tolerance to nitrite exposure in mature M. rosenbergii and/or the competitive effects of chloride ions. Taken together, these results showed that ammonia and nitrite caused a series of combined oxidative stress and apoptosis in M. rosenbergi, but further studies are of great need to explain the mechanisms.
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Affiliation(s)
- Yufan Zhang
- Key Laboratory of Ecology and Environmental Science in Guangdong Higher Education, Key Laboratory of Safe and Healthy Aquaculture in Guangdong Province, College of Life Science, South China Normal University, Guangzhou, 510631, People's Republic of China
| | - Chaoxia Ye
- Key Laboratory of Ecology and Environmental Science in Guangdong Higher Education, Key Laboratory of Safe and Healthy Aquaculture in Guangdong Province, College of Life Science, South China Normal University, Guangzhou, 510631, People's Republic of China.
| | - Anli Wang
- Key Laboratory of Ecology and Environmental Science in Guangdong Higher Education, Key Laboratory of Safe and Healthy Aquaculture in Guangdong Province, College of Life Science, South China Normal University, Guangzhou, 510631, People's Republic of China.
| | - Xuan Zhu
- Key Laboratory of Ecology and Environmental Science in Guangdong Higher Education, Key Laboratory of Safe and Healthy Aquaculture in Guangdong Province, College of Life Science, South China Normal University, Guangzhou, 510631, People's Republic of China
| | - Changhong Chen
- Key Laboratory of Ecology and Environmental Science in Guangdong Higher Education, Key Laboratory of Safe and Healthy Aquaculture in Guangdong Province, College of Life Science, South China Normal University, Guangzhou, 510631, People's Republic of China
| | - Jianan Xian
- Key Laboratory of Ecology and Environmental Science in Guangdong Higher Education, Key Laboratory of Safe and Healthy Aquaculture in Guangdong Province, College of Life Science, South China Normal University, Guangzhou, 510631, People's Republic of China
| | - Zhenzhu Sun
- Key Laboratory of Ecology and Environmental Science in Guangdong Higher Education, Key Laboratory of Safe and Healthy Aquaculture in Guangdong Province, College of Life Science, South China Normal University, Guangzhou, 510631, People's Republic of China
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Shepherd AI, Gilchrist M, Winyard PG, Jones AM, Hallmann E, Kazimierczak R, Rembialkowska E, Benjamin N, Shore AC, Wilkerson DP. Effects of dietary nitrate supplementation on the oxygen cost of exercise and walking performance in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled crossover trial. Free Radic Biol Med 2015; 86:200-8. [PMID: 25998421 DOI: 10.1016/j.freeradbiomed.2015.05.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 04/20/2015] [Accepted: 05/11/2015] [Indexed: 12/16/2022]
Abstract
Dietary nitrate supplementation has been shown to reduce the oxygen (O2) cost of exercise and enhance exercise tolerance in healthy individuals. This study assessed whether similar effects could be observed in individuals with type 2 diabetes (T2DM). In a randomized, double-blind, placebo-controlled crossover study, 48 participants with T2DM supplemented their diet for 4 days with either nitrate-rich beetroot juice (70ml/day, 6.43mmol nitrate/day) or nitrate-depleted beetroot juice as placebo (70ml/day, 0.07mmol nitrate/day). After each intervention period, resting plasma nitrate and nitrite concentrations were measured subsequent to participants completing moderate-paced walking. Pulmonary gas exchange was measured to assess the O2 cost of walking. After a rest period, participants performed the 6-min walk test (6MWT). Relative to placebo, beetroot juice resulted in a significant increase in plasma nitrate (placebo, 57±66 vs beetroot, 319±110µM; P < 0.001) and plasma nitrite concentration (placebo, 680±256 vs beetroot, 1065±607nM; P < 0.001). There were no differences between placebo juice and beetroot juice for the O2 cost of walking (946±221 vs 939±223ml/min, respectively; P = 0.59) and distance covered in the 6MWT (550±83 vs 554±90m, respectively; P = 0.17). Nitrate supplementation did not affect the O2 cost of moderate-paced walking or improve performance in the 6MWT. These findings indicate that dietary nitrate supplementation does not modulate the response to exercise in individuals with T2DM.
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Affiliation(s)
- Anthony I Shepherd
- College of Life and Environmental Sciences, Sport and Health Sciences, University of Exeter, Exeter EX1 2LU, Devon, UK; University of Exeter Medical School and NIHR Exeter Clinical Research Facility, Royal Devon and Exeter Hospital, Exeter, Devon, UK
| | - Mark Gilchrist
- University of Exeter Medical School and NIHR Exeter Clinical Research Facility, Royal Devon and Exeter Hospital, Exeter, Devon, UK
| | - Paul G Winyard
- University of Exeter Medical School and NIHR Exeter Clinical Research Facility, Royal Devon and Exeter Hospital, Exeter, Devon, UK
| | - Andrew M Jones
- College of Life and Environmental Sciences, Sport and Health Sciences, University of Exeter, Exeter EX1 2LU, Devon, UK
| | | | | | | | - Nigel Benjamin
- University of Exeter Medical School and NIHR Exeter Clinical Research Facility, Royal Devon and Exeter Hospital, Exeter, Devon, UK
| | - Angela C Shore
- University of Exeter Medical School and NIHR Exeter Clinical Research Facility, Royal Devon and Exeter Hospital, Exeter, Devon, UK
| | - Daryl P Wilkerson
- College of Life and Environmental Sciences, Sport and Health Sciences, University of Exeter, Exeter EX1 2LU, Devon, UK.
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38
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Affourtit C, Bailey SJ, Jones AM, Smallwood MJ, Winyard PG. On the mechanism by which dietary nitrate improves human skeletal muscle function. Front Physiol 2015; 6:211. [PMID: 26283970 PMCID: PMC4518145 DOI: 10.3389/fphys.2015.00211] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 07/14/2015] [Indexed: 12/26/2022] Open
Abstract
Inorganic nitrate is present at high levels in beetroot and celery, and in green leafy vegetables such as spinach and lettuce. Though long believed inert, nitrate can be reduced to nitrite in the human mouth and, further, under hypoxia and/or low pH, to nitric oxide. Dietary nitrate has thus been associated favorably with nitric-oxide-regulated processes including blood flow and energy metabolism. Indeed, the therapeutic potential of dietary nitrate in cardiovascular disease and metabolic syndrome-both aging-related medical disorders-has attracted considerable recent research interest. We and others have shown that dietary nitrate supplementation lowers the oxygen cost of human exercise, as less respiratory activity appears to be required for a set rate of skeletal muscle work. This striking observation predicts that nitrate benefits the energy metabolism of human muscle, increasing the efficiency of either mitochondrial ATP synthesis and/or of cellular ATP-consuming processes. In this mini-review, we evaluate experimental support for the dietary nitrate effects on muscle bioenergetics and we critically discuss the likelihood of nitric oxide as the molecular mediator of such effects.
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Affiliation(s)
- Charles Affourtit
- School of Biomedical and Healthcare Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University Plymouth, UK
| | - Stephen J Bailey
- Department of Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter Exeter, UK
| | - Andrew M Jones
- Department of Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter Exeter, UK
| | - Miranda J Smallwood
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter Exeter, UK
| | - Paul G Winyard
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter Exeter, UK
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Lee JS, Stebbins CL, Jung E, Nho H, Kim JK, Chang MJ, Choi HM. Effects of chronic dietary nitrate supplementation on the hemodynamic response to dynamic exercise. Am J Physiol Regul Integr Comp Physiol 2015; 309:R459-66. [PMID: 26084693 DOI: 10.1152/ajpregu.00099.2015] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 06/13/2015] [Indexed: 01/08/2023]
Abstract
While acute treatment with beetroot juice (BRJ) containing nitrate (NO3 (-)) can lower systolic blood pressure (SBP), afterload, and myocardial O2 demand during submaximal exercise, effects of chronic supplementation with BRJ (containing a relatively low dose of NO3 (-), 400 mg) on cardiac output (CO), SBP, total peripheral resistance (TPR), and the work of the heart in response to dynamic exercise are not known. Thus, in 14 healthy males (22 ± 1 yr), we compared effects of 15 days of both BRJ and nitrate-depleted beetroot juice (NDBRJ) supplementation on plasma concentrations of NOx (NO3 (-)/NO2 (-)), SBP, diastolic blood pressure (DBP), mean arterial pressure (MAP), CO, TPR, and rate pressure product (RPP) at rest and during progressive cycling exercise. Endothelial function was also assessed via flow-mediated dilation (FMD). BRJ supplementation increased plasma NOx from 83.8 ± 13.8 to 167.6 ± 13.2 μM. Compared with NDBRJ, BRJ reduced SBP, DBP, MAP, and TPR at rest and during exercise (P < 0.05). In addition, RPP was decreased during exercise, while CO was increased, but only at rest and the 30% workload (P < 0.05). BRJ enhanced FMD-induced increases in brachial artery diameter (pre: 12.3 ± 1.6%; post: 17.8 ± 1.9%). We conclude that 1) chronic supplementation with BRJ lowers blood pressure and vascular resistance at rest and during exercise and attenuates RPP during exercise and 2) these effects may be due, in part, to enhanced endothelium-induced vasodilation in contracting skeletal muscle. Findings suggest that BRJ can act as a dietary nutraceutical capable of enhancing O2 delivery and reducing work of the heart, such that exercise can be performed at a given workload for a longer period of time before the onset of fatigue.
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Affiliation(s)
- Jae-Seok Lee
- Graduate School of Physical Education, Kyung Hee University, Seoul, South Korea; and
| | - Charles L Stebbins
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of California at Davis, Davis, California
| | - Eunji Jung
- Graduate School of Physical Education, Kyung Hee University, Seoul, South Korea; and
| | - Hosung Nho
- Graduate School of Physical Education, Kyung Hee University, Seoul, South Korea; and
| | - Jong-Kyung Kim
- Graduate School of Physical Education, Kyung Hee University, Seoul, South Korea; and
| | - Myoung-Jei Chang
- Graduate School of Physical Education, Kyung Hee University, Seoul, South Korea; and
| | - Hyun-Min Choi
- Graduate School of Physical Education, Kyung Hee University, Seoul, South Korea; and
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40
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Beltran-Povea A, Caballano-Infantes E, Salguero-Aranda C, Martín F, Soria B, Bedoya FJ, Tejedo JR, Cahuana GM. Role of nitric oxide in the maintenance of pluripotency and regulation of the hypoxia response in stem cells. World J Stem Cells 2015; 7:605-617. [PMID: 25914767 PMCID: PMC4404395 DOI: 10.4252/wjsc.v7.i3.605] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 11/13/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Stem cell pluripotency and differentiation are global processes regulated by several pathways that have been studied intensively over recent years. Nitric oxide (NO) is an important molecule that affects gene expression at the level of transcription and translation and regulates cell survival and proliferation in diverse cell types. In embryonic stem cells NO has a dual role, controlling differentiation and survival, but the molecular mechanisms by which it modulates these functions are not completely defined. NO is a physiological regulator of cell respiration through the inhibition of cytochrome c oxidase. Many researchers have been examining the role that NO plays in other aspects of metabolism such as the cellular bioenergetics state, the hypoxia response and the relationship of these areas to stem cell stemness.
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Abstract
SIGNIFICANCE Mitochondria utilize most of the oxygen to produce adenosine triphosphate via electron transfer coupled with oxidative phosphorylation. Hypoxia undoubtedly induces reduced energy production via decreased mitochondrial metabolic activity or altered hypoxia-inducible factor-1- and peroxisome proliferator-activated receptor gamma coactivator 1-dependent mitochondrial biogenesis. Hypoxia may also activate mitophagy to selectively remove damaged or unwanted mitochondria for both mitochondrial quantity and quality control. Increasing evidence has shown that the accumulation of damaged mitochondria is a characteristic of aging and aging-related diseases, such as metabolic disorder, cancer, and neurodegenerative disease. RECENT ADVANCES Both receptor-dependent and PTEN-induced putative kinase 1-PARKIN-dependent mitophagy have been described. Mitophagy receptors include Atg32 in yeast, as well as NIX/BNIP3L, B-cell lymphoma 2/adenovirus E1B 19-kDa-interacting protein 3 and FUN14 domain containing 1 in mammals. In response to hypoxia or mitochondrial oxidative stress, receptor-mediated mitophagy was found to be activated via both transcriptional and post-translational modification. CRITICAL ISSUES To date, the molecular mechanisms by which hypoxia triggers mitophagy and by which mitophagy contributes to the pathogenesis of aging-related diseases remain to be explored. FUTURE DIRECTIONS An improved understanding of the regulation of mitochondrial quality may provide a strategy for treating aging-related diseases by targeting mitochondria and mitophagy pathways.
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Affiliation(s)
- Hao Wu
- 1 State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology , Chinese Academy of Sciences, Beijing, China
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42
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The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med 2015; 13:68. [PMID: 25889215 PMCID: PMC4382850 DOI: 10.1186/s12916-015-0310-y] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 03/04/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Mitochondrial dysfunction and defects in oxidative metabolism are a characteristic feature of many chronic illnesses not currently classified as mitochondrial diseases. Examples of such illnesses include bipolar disorder, multiple sclerosis, Parkinson's disease, schizophrenia, depression, autism, and chronic fatigue syndrome. DISCUSSION While the majority of patients with multiple sclerosis appear to have widespread mitochondrial dysfunction and impaired ATP production, the findings in patients diagnosed with Parkinson's disease, autism, depression, bipolar disorder schizophrenia and chronic fatigue syndrome are less consistent, likely reflecting the fact that these diagnoses do not represent a disease with a unitary pathogenesis and pathophysiology. However, investigations have revealed the presence of chronic oxidative stress to be an almost invariant finding in study cohorts of patients afforded each diagnosis. This state is characterized by elevated reactive oxygen and nitrogen species and/or reduced levels of glutathione, and goes hand in hand with chronic systemic inflammation with elevated levels of pro-inflammatory cytokines. SUMMARY This paper details mechanisms by which elevated levels of reactive oxygen and nitrogen species together with elevated pro-inflammatory cytokines could conspire to pave a major road to the development of mitochondrial dysfunction and impaired oxidative metabolism seen in many patients diagnosed with these disorders.
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43
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Apostolova N, Victor VM. Molecular strategies for targeting antioxidants to mitochondria: therapeutic implications. Antioxid Redox Signal 2015; 22:686-729. [PMID: 25546574 PMCID: PMC4350006 DOI: 10.1089/ars.2014.5952] [Citation(s) in RCA: 192] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules.
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Affiliation(s)
- Nadezda Apostolova
- 1 Faculty of Health Sciences, University Jaume I , Castellón de la Plana, Spain
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44
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Sansbury BE, Bhatnagar A, Hill BG. Impact of nutrient excess and endothelial nitric oxide synthase on the plasma metabolite profile in mice. Front Physiol 2014; 5:453. [PMID: 25505420 PMCID: PMC4243488 DOI: 10.3389/fphys.2014.00453] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 11/03/2014] [Indexed: 01/08/2023] Open
Abstract
An increase in calorie consumption is associated with the recent rise in obesity prevalence. However, our current understanding of the effects of nutrient excess on major metabolic pathways appears insufficient to develop safe and effective metabolic interventions to prevent obesity. Hence, we sought to identify systemic metabolic changes caused by nutrient excess and to determine how endothelial nitric oxide synthase (eNOS)—which has anti-obesogenic properties—affects systemic metabolism by measuring plasma metabolites. Wild-type (WT) and eNOS transgenic (eNOS-TG) mice were placed on low fat or high fat diets for 6 weeks, and plasma metabolites were measured using an unbiased metabolomic approach. High fat feeding in WT mice led to significant increases in fat mass, which was associated with significantly lower plasma levels of 1,5-anhydroglucitol, lysophospholipids, 3-dehydrocarnitine, and bile acids, as well as branched chain amino acids (BCAAs) and their metabolites. Plasma levels of several lipids including sphingomyelins, stearoylcarnitine, dihomo-linoleate and metabolites associated with oxidative stress were increased by high fat diet. In comparison with low fat-fed WT mice, eNOS-TG mice showed lower levels of several free fatty acids, but in contrast, the levels of bile acids, amino acids, and BCAA catabolites were increased. When placed on a high fat diet, eNOS overexpressing mice showed remarkably higher levels of plasma bile acids and elevated levels of plasma BCAAs and their catabolites compared with WT mice. Treatment with GW4064, an inhibitor of bile acid synthesis, decreased plasma bile acid levels but was not sufficient to reverse the anti-obesogenic effects of eNOS overexpression. These findings reveal unique metabolic changes in response to high fat diet and eNOS overexpression and suggest that the anti-obesity effects of eNOS are likely independent of changes in the bile acid pool.
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Affiliation(s)
- Brian E Sansbury
- Division of Cardiology, Department of Medicine, Institute of Molecular Cardiology, University of Louisville Louisville, KY, USA ; Department of Medicine, Diabetes and Obesity Center, University of Louisville Louisville, KY, USA ; Department of Physiology and Biophysics, University of Louisville Louisville, KY, USA
| | - Aruni Bhatnagar
- Division of Cardiology, Department of Medicine, Institute of Molecular Cardiology, University of Louisville Louisville, KY, USA ; Department of Medicine, Diabetes and Obesity Center, University of Louisville Louisville, KY, USA ; Department of Physiology and Biophysics, University of Louisville Louisville, KY, USA ; Department of Biochemistry and Molecular Biology, University of Louisville Louisville, KY, USA
| | - Bradford G Hill
- Division of Cardiology, Department of Medicine, Institute of Molecular Cardiology, University of Louisville Louisville, KY, USA ; Department of Medicine, Diabetes and Obesity Center, University of Louisville Louisville, KY, USA ; Department of Physiology and Biophysics, University of Louisville Louisville, KY, USA ; Department of Biochemistry and Molecular Biology, University of Louisville Louisville, KY, USA
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45
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Sansbury BE, Hill BG. Regulation of obesity and insulin resistance by nitric oxide. Free Radic Biol Med 2014; 73:383-99. [PMID: 24878261 PMCID: PMC4112002 DOI: 10.1016/j.freeradbiomed.2014.05.016] [Citation(s) in RCA: 186] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 05/16/2014] [Accepted: 05/17/2014] [Indexed: 02/07/2023]
Abstract
Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a worldwide pandemic with few tangible and safe treatment options. Although it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many "distal" causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity-those that directly regulate energy metabolism or caloric intake-seem to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin-resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease.
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Affiliation(s)
- Brian E Sansbury
- Diabetes and Obesity Center, Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Bradford G Hill
- Diabetes and Obesity Center, Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
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46
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Kelly J, Vanhatalo A, Wilkerson DP, Wylie LJ, Jones AM. Effects of nitrate on the power-duration relationship for severe-intensity exercise. Med Sci Sports Exerc 2014; 45:1798-806. [PMID: 23475164 DOI: 10.1249/mss.0b013e31828e885c] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
PURPOSE The power asymptote (critical power [CP]) and curvature constant (W') of the power-duration relationship dictate the tolerance to severe-intensity exercise. We tested the hypothesis that dietary nitrate supplementation would increase the CP and/or the W' during cycling exercise. METHODS In a double-blind, randomized, crossover study, nine recreationally active male subjects supplemented their diet with either nitrate-rich concentrated beetroot juice (BR; 2 × 250 mL·d, ∼8.2 mmol·d nitrate) or a nitrate-depleted BR placebo (PL; 2 × 250 mL·d, ∼0.006 mmol·d nitrate). In each condition, the subjects completed four separate severe-intensity exercise bouts to exhaustion at 60% of the difference between the gas exchange threshold and the peak power attained during incremental exercise (60% Δ), 70% Δ, 80% Δ, and 100% peak power, and the results were used to establish CP and W'. RESULTS Nitrate supplementation improved exercise tolerance during exercise at 60% Δ (BR, 696 ± 120 vs PL, 593 ± 68 s; P < 0.05), 70% Δ (BR, 452 ± 106 vs PL, 390 ± 86 s; P < 0.05), and 80% Δ (BR, 294 ± 50 vs PL, 263 ± 50 s; P < 0.05) but not 100% peak power (BR, 182 ± 37 vs PL, 166 ± 26 s; P = 0.10). Neither CP (BR, 221 ± 27 vs PL, 218 ± 26 W) nor W' (BR, 19.3 ± 4.6 vs PL, 17.8 ± 3 kJ) were significantly altered by BR. CONCLUSION Dietary nitrate supplementation improved endurance during severe-intensity exercise in recreationally active subjects without significantly increasing either the CP or the W'.
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Affiliation(s)
- James Kelly
- College of Life and Environmental Sciences, University of Exeter, Exeter, UK
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Ergin B, Kapucu A, Demirci-Tansel C, Ince C. The renal microcirculation in sepsis. Nephrol Dial Transplant 2014; 30:169-77. [PMID: 24848133 DOI: 10.1093/ndt/gfu105] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Despite identification of several cellular mechanisms being thought to underlie the development of septic acute kidney injury (AKI), the pathophysiology of the occurrence of AKI is still poorly understood. It is clear, however, that instead of a single mechanism being responsible for its aetiology, an orchestra of cellular mechanisms failing is associated with AKI. The integrative physiological compartment where these mechanisms come together and exert their integrative deleterious action is the renal microcirculation (MC). This is why it is opportune to review the response of the renal MC to sepsis and discuss the determinants of its (dys)function and how it contributes to the pathogenesis of renal failure. A main determinant of adequate organ function is the adequate supply and utilization of oxygen at the microcirculatory and cellular level to perform organ function. The highly complex architecture of the renal microvasculature, the need to meet a high energy demand and the fact that the kidney is borderline ischaemic makes the kidney a highly vulnerable organ to hypoxaemic injury. Under normal, steady-state conditions, oxygen (O2) supply to the renal tissues is well regulated; however, under septic conditions the delicate balance of oxygen supply versus demand is disturbed due to renal microvasculature dysfunction. This dysfunction is largely due to the interaction of renal oxygen handling, nitric oxide metabolism and radical formation. Renal tissue oxygenation is highly heterogeneous not only between the cortex and medulla but also within these renal compartments. Integrative evaluation of the different determinants of tissue oxygen in sepsis models has identified the deterioration of microcirculatory oxygenation as a key component in the development AKI. It is becoming clear that resuscitation of the failing kidney needs to integratively correct the homeostasis between oxygen, and reactive oxygen and nitrogen species. Several experimental therapeutic modalities have been found to be effective in restoring microcirculatory oxygenation in parallel to improving renal function following septic AKI. However, these have to be verified in clinical studies. The development of clinical physiological biomarkers of AKI specifically aimed at the MC should form a valuable contribution to monitoring such new therapeutic modalities.
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Affiliation(s)
- Bulent Ergin
- Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands
| | - Aysegul Kapucu
- Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands Department of Biology and Zoology Division, University of Istanbul, Istanbul, Turkey
| | - Cihan Demirci-Tansel
- Department of Biology and Zoology Division, University of Istanbul, Istanbul, Turkey
| | - Can Ince
- Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands
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Babot M, Birch A, Labarbuta P, Galkin A. Characterisation of the active/de-active transition of mitochondrial complex I. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2014; 1837:1083-92. [PMID: 24569053 PMCID: PMC4331042 DOI: 10.1016/j.bbabio.2014.02.018] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 02/14/2014] [Accepted: 02/17/2014] [Indexed: 12/12/2022]
Abstract
Oxidation of NADH in the mitochondrial matrix of aerobic cells is catalysed by mitochondrial complex I. The regulation of this mitochondrial enzyme is not completely understood. An interesting characteristic of complex I from some organisms is the ability to adopt two distinct states: the so-called catalytically active (A) and the de-active, dormant state (D). The A-form in situ can undergo de-activation when the activity of the respiratory chain is limited (i.e. in the absence of oxygen). The mechanisms and driving force behind the A/D transition of the enzyme are currently unknown, but several subunits are most likely involved in the conformational rearrangements: the accessory subunit 39 kDa (NDUFA9) and the mitochondrially encoded subunits, ND3 and ND1. These three subunits are located in the region of the quinone binding site. The A/D transition could represent an intrinsic mechanism which provides a fast response of the mitochondrial respiratory chain to oxygen deprivation. The physiological role of the accumulation of the D-form in anoxia is most probably to protect mitochondria from ROS generation due to the rapid burst of respiration following reoxygenation. The de-activation rate varies in different tissues and can be modulated by the temperature, the presence of free fatty acids and divalent cations, the NAD+/NADH ratio in the matrix, the presence of nitric oxide and oxygen availability. Cysteine-39 of the ND3 subunit, exposed in the D-form, is susceptible to covalent modification by nitrosothiols, ROS and RNS. The D-form in situ could react with natural effectors in mitochondria or with pharmacological agents. Therefore the modulation of the re-activation rate of complex I could be a way to ameliorate the ischaemia/reperfusion damage. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference. Guest Editors: Manuela Pereira and Miguel Teixeira.
The potential mechanism of complex I A/D transition is discussed. An —SH group exposed in the D-form is susceptible to covalent modification. The role of A/D transition in tissue response to ischaemia is proposed.
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Affiliation(s)
- Marion Babot
- Queen's University Belfast, School of Biological Sciences, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Amanda Birch
- Queen's University Belfast, School of Biological Sciences, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Paola Labarbuta
- Queen's University Belfast, School of Biological Sciences, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Alexander Galkin
- Queen's University Belfast, School of Biological Sciences, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
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Cytochrome bd oxidase and bacterial tolerance to oxidative and nitrosative stress. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2014; 1837:1178-87. [PMID: 24486503 DOI: 10.1016/j.bbabio.2014.01.016] [Citation(s) in RCA: 146] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 01/25/2014] [Accepted: 01/27/2014] [Indexed: 12/28/2022]
Abstract
Cytochrome bd is a prokaryotic respiratory quinol:O2 oxidoreductase, phylogenetically unrelated to the extensively studied heme-copper oxidases (HCOs). The enzyme contributes to energy conservation by generating a proton motive force, though working with a lower energetic efficiency as compared to HCOs. Relevant to patho-physiology, members of the bd-family were shown to promote virulence in some pathogenic bacteria, which makes these enzymes of interest also as potential drug targets. Beyond its role in cell bioenergetics, cytochrome bd accomplishes several additional physiological functions, being apparently implicated in the response of the bacterial cell to a number of stress conditions. Compelling experimental evidence suggests that the enzyme enhances bacterial tolerance to oxidative and nitrosative stress conditions, owing to its unusually high nitric oxide (NO) dissociation rate and a notable catalase activity; the latter has been recently documented in one of the two bd-type oxidases of Escherichia coli. Current knowledge on cytochrome bd and its reactivity with O2, NO and H2O2 is summarized in this review in the light of the hypothesis that the preferential (over HCOs) expression of cytochrome bd in pathogenic bacteria may represent a strategy to evade the host immune attack based on production of NO and reactive oxygen species (ROS). This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.
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50
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Umbrello M, Dyson A, Pinto BB, Fernandez BO, Simon V, Feelisch M, Singer M. Short-term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction. J Physiol 2014; 592:1061-75. [PMID: 24396056 DOI: 10.1113/jphysiol.2013.255687] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Local increases in blood flow--'hypoxic vasodilation'--confer cellular protection in the face of reduced oxygen delivery. The physiological relevance of this response is well established, yet ongoing controversy surrounds its underlying mechanisms. We sought to confirm that early hypoxic vasodilation is a nitric oxide (NO)-mediated phenomenon and to study putative pathways for increased levels of NO, namely production from NO synthases, intravascular nitrite reduction, release from preformed stores and reduced deactivation by cytochrome c oxidase. Experiments were performed on spontaneously breathing, anaesthetized, male Wistar rats undergoing short-term systemic hypoxaemia, who received pharmacological inhibitors and activators of the various NO pathways. Arterial blood pressure, cardiac output, tissue oxygen tension and the circulating pool of NO metabolites (oxidation, nitrosation and nitrosylation products) were measured in plasma and erythrocytes. Hypoxaemia caused a rapid and sustained vasodilation, which was only partially reversed by non-selective NO synthase inhibition. This was associated with significantly lower plasma nitrite, and marginally elevated nitrate levels, suggestive of nitrite bioinactivation. Administration of sodium nitrite had little effect in normoxia, but produced significant vasodilation and increased nitrosylation during hypoxaemia that could not be reversed by NO scavenging. Methodological issues prevented assessment of the contribution, if any, of reduced deactivation of NO by cytochrome c oxidase. In conclusion, acute hypoxic vasodilation is an adaptive NO-mediated response conferred through bioactive metabolites rather than free NO from haemoglobin-mediated reduction of nitrite.
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Affiliation(s)
- Michele Umbrello
- Bloomsbury Institute of Intensive Care Medicine, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
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