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Chiletti R, Fincher SH, Horton SB, Peek GJ, Checchia P, Butt W. The Role of Nitric Oxide in the Sweep Gas for Patients Receiving Extracorporeal Membrane Oxygenation or Cardiopulmonary Bypass. Can J Cardiol 2025; 41:621-629. [PMID: 39733940 DOI: 10.1016/j.cjca.2024.12.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/14/2024] [Accepted: 12/21/2024] [Indexed: 12/31/2024] Open
Abstract
Nitric oxide (NO) was proclaimed the 1992 "molecule of the year" by Culotta in Science magazine because of its importance in neuroscience, physiology, and immunology. Inhaled NO has been in clinical use for over 35 years to decrease pulmonary hypertension and improve oxygenation. Over the past 20 years, there has been much research into understanding the role of NO on cell surface receptors, mitochondria, and intracellular processes that involve calcium and superoxide radicals. This research has shown that, irrespective of the cause, NO has a major role in the systemic inflammatory response syndrome and ischemia-reperfusion injury.1 More recent clinical research has focussed on NO use in patients undergoing cardiopulmonary bypass and receiving extracorporeal life support, with some centres incorporating NO into sweep gas as part of routine practice. In this article we review NO pathways in humans, the biologic effects of NO, the interplay between NO and red blood cells, and animal and human studies on the effects of exogenously administered NO.
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Affiliation(s)
- Roberto Chiletti
- Department of Paediatric Intensive Care, Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Sophie H Fincher
- Department of Paediatric Intensive Care, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Critical Care, Faculty of Medicine, Dentistry & Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
| | - Stephen B Horton
- Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry & Health Sciences, University of Melbourne, Melbourne, Victoria, Australia; Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Giles J Peek
- Congenital Heart Centre, University of Florida, Gainesville, Florida, USA
| | - Paul Checchia
- Division of Critical Care Medicine, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA
| | - Warwick Butt
- Department of Paediatric Intensive Care, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Critical Care, Faculty of Medicine, Dentistry & Health Sciences, University of Melbourne, Melbourne, Victoria, Australia; ICU Research Clinical Sciences Theme MCRI, Melbourne, Victoria, Australia.
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Grimmett ZW, Zhang R, Zhou HL, Chen Q, Miller D, Qian Z, Lin J, Kalra R, Gross SS, Koch WJ, Premont RT, Stamler JS. The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.12.642752. [PMID: 40161620 PMCID: PMC11952481 DOI: 10.1101/2025.03.12.642752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Acute myocardial infarction (MI) is a leading cause of morbidity and mortality, and therapeutic options remain limited. Endogenously generated nitric oxide (NO) is highly cardioprotective, but protection is not replicated by nitroso-vasodilators (e.g., nitrates, nitroprusside) used in clinical practice, highlighting specificity in NO-based signaling and untapped therapeutic potential. Signaling by NO is mediated largely by S-nitrosylation, entailing specific enzymes that form and degrade S-nitrosothiols in proteins (SNO-proteins), termed nitrosylases and denitrosylases, respectively. SNO-CoA Reductase 2 (SCoR2; product of the Akr1a1 gene) is a recently discovered protein denitrosylase. Genetic variants in SCoR2 have been associated with cardiovascular disease, but its function is unknown. Here we show that mice lacking SCoR2 exhibit robust protection in an animal model of MI. SCoR2 regulates ketolytic energy availability, antioxidant levels and polyol homeostasis via S-nitrosylation of key metabolic effectors. Human cardiomyopathy shows reduced SCoR2 expression and an S-nitrosylation signature of metabolic reprogramming, mirroring SCoR2-/- mice. Deletion of SCoR2 thus coordinately reprograms multiple metabolic pathways-ketone body utilization, glycolysis, pentose phosphate shunt and polyol metabolism-to limit infarct size, establishing SCoR2 as a novel regulator in the injured myocardium and a potential drug target. Impact statement Mice lacking the denitrosylase enzyme SCoR2/AKR1A1 demonstrate robust cardioprotection resulting from reprogramming of multiple metabolic pathways, revealing widespread, coordinated metabolic regulation by SCoR2.
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Affiliation(s)
- Zachary W. Grimmett
- Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland OH, 44106
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH, 44106
| | - Rongli Zhang
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH, 44106
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland OH, 44106
| | - Hua-Lin Zhou
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH, 44106
| | - Qiuying Chen
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065
| | - Dawson Miller
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065
| | - Zhaoxia Qian
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH, 44106
| | - Justin Lin
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH, 44106
| | - Riti Kalra
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH, 44106
| | - Steven S. Gross
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065
| | - Walter J. Koch
- Department of Surgery, Duke University School of Medicine, Durham NC, 27710
- Department of Medicine, Duke University School of Medicine, Durham NC, 27710
| | - Richard T. Premont
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH, 44106
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland OH, 44106
| | - Jonathan S. Stamler
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland OH, 44106
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland OH, 44106
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Jeddi S, Yousefzadeh N, Zarkesh M, Kashfi K, Ghasemi A. Effect of long-term inorganic nitrate administration on myocardial ischemia-reperfusion injury in ovariectomized rats. Front Pharmacol 2024; 15:1369379. [PMID: 38601460 PMCID: PMC11004245 DOI: 10.3389/fphar.2024.1369379] [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: 01/12/2024] [Accepted: 03/15/2024] [Indexed: 04/12/2024] Open
Abstract
Introduction: Menopause is associated with reduced nitric oxide (NO) bioavailability and lower tolerance against myocardial ischemia-reperfusion (IR) injury. This study investigated whether long-term nitrate administration provides resistance against myocardial IR injury in ovariectomized (OVX) rats. Method: After ovariectomy, female rats were assigned to the OVX and the OVX + nitrate groups (n = 14/group); the latter group consumed nitrate (100 mg/L) for 9 months. At month 9, each group was divided into two subgroups (n = 7/subgroup), of which one subgroup was exposed to myocardial IR (IR+ hearts) and the other was not exposed (IR- hearts). The hearts of rats were isolated, and NO metabolite (NOx), oxidative stress indices, and mRNA expressions of endothelial (eNOS), inducible (iNOS), and neuronal (nNOS) NO synthases, as well as markers of apoptosis, were measured in the IR- and IR+ hearts. In the IR+ hearts, cardiac function indices (CFI) and the infarct size were also measured. Results: Nitrate increased catalase activity (97%) and eNOS expression (2.94-fold) in the IR- hearts. In the IR+ hearts, nitrate reduced left ventricular (LV) end-diastolic pressure (11.6%) and infarct size (26.2%) and increased recovery of LV developed pressure (44.0%) and peak rate of positive (28.9%) and negative (15.4%) changes in LV pressure. In addition, in the IR+ hearts, nitrate increased eNOS and B-cell lymphoma-2 (Bcl-2) as well as decreased iNOS, Bcl-2 associated X protein (Bax), caspase-3, caspase-8, caspase-9, and tumor necrosis factor-α (TNF-α) expression. Nitrate increased total antioxidant capacity (TAC) and catalase (CAT) activity and decreased malondialdehyde (MDA) levels at month nine in serum and IR+ hearts. Conclusion: The favorable effects of nitrate against IR injury were associated with higher eNOS and Bcl-2 expression, CAT activity, TAC, and lower iNOS, Bax, caspase-3, caspase-8, caspase-9 and TNF-α expression, and MDA in the heart tissue. Nitrate preconditioning alleviated IR-induced myocardial injury in OVX rats; this effect was associated with eNOS upregulation before IR and the blunting of OVX-induced eNOS downregulation, iNOS upregulation, apoptosis, and oxidative stress in heart tissue after IR.
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Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasibeh Yousefzadeh
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Zarkesh
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, United States
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Yassaghi Y, Jeddi S, Kashfi K, Ghasemi A. Myocardial infarct size is reduced by nitrite and nitrate administration: a systematic review and meta-analysis of animal studies. EXCLI JOURNAL 2024; 23:18-33. [PMID: 38357094 PMCID: PMC10864704 DOI: 10.17179/excli2023-6740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 12/18/2023] [Indexed: 02/16/2024]
Abstract
Ischemic heart disease (IHD) is the leading cause of mortality worldwide and can be complicated by myocardial infarction (MI), leading to cardiac failure. Inorganic nitrite and nitrate, which release nitric oxide (NO), can protect the heart against myocardial injury. This animal systematic review and meta-analysis aims to assess whether the administration of nitrite/nitrate decreases myocardial infarct size. We systematically searched PubMed, Scopus, and Web of Science databases until October 2023; 15 eligible animal studies (35 study arms for in-vivo and 10 for in-vitro studies) published between 1989 and 2023 were included. In-vivo studies were conducted on rats, mice, cats, and dogs, and in-vitro studies on rats and mice with an overall exposure of 0.03 to 12713 mg/kg to nitrate/nitrite administrated before, after, or during ischemia mainly by intravenous single bolus or by oral over 270 days. All in-vitro studies used nitrite/nitrate before ischemia, with the concentration ranging between 0.34 to 201 μM. MI was induced by occlusion of the left anterior diagonal or left circumflex arteries in in-vitro studies and by isoproterenol in in-vivo studies. Infarct size was measured by direct staining of the sliced heart sections. In in-vivo studies, nitrite (overall effect size (ES)=-17.0 %, 95 % confidence interval (CI)=-21.3, -12.8, P<0.001) and nitrate (overall ES= -9.6 %, 95 % CI=-15.7, -3.4, P=0.002) reduced myocardial infarct size. In in-vitro studies, nitrite (overall ES=-15.8 %, 95 % CI=-25.5, -6.2, P=0.001) reduced the infarct size. Sensitivity analysis showed that the overall effect of nitrite on myocardial infarct size was unaffected by doses or health conditions in in-vivo and in-vitro studies. In conclusion, our meta-analysis showed that nitrite/nitrate administration can effectively reduce myocardial infarct size. However, these results should be approached with caution because of the limitations of animal studies and the existing high heterogeneity.
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Affiliation(s)
- Younes Yassaghi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Maia LB. Bringing Nitric Oxide to the Molybdenum World-A Personal Perspective. Molecules 2023; 28:5819. [PMID: 37570788 PMCID: PMC10420851 DOI: 10.3390/molecules28155819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/29/2023] [Accepted: 07/30/2023] [Indexed: 08/13/2023] Open
Abstract
Molybdenum-containing enzymes of the xanthine oxidase (XO) family are well known to catalyse oxygen atom transfer reactions, with the great majority of the characterised enzymes catalysing the insertion of an oxygen atom into the substrate. Although some family members are known to catalyse the "reverse" reaction, the capability to abstract an oxygen atom from the substrate molecule is not generally recognised for these enzymes. Hence, it was with surprise and scepticism that the "molybdenum community" noticed the reports on the mammalian XO capability to catalyse the oxygen atom abstraction of nitrite to form nitric oxide (NO). The lack of precedent for a molybdenum- (or tungsten) containing nitrite reductase on the nitrogen biogeochemical cycle contributed also to the scepticism. It took several kinetic, spectroscopic and mechanistic studies on enzymes of the XO family and also of sulfite oxidase and DMSO reductase families to finally have wide recognition of the molybdoenzymes' ability to form NO from nitrite. Herein, integrated in a collection of "personal views" edited by Professor Ralf Mendel, is an overview of my personal journey on the XO and aldehyde oxidase-catalysed nitrite reduction to NO. The main research findings and the path followed to establish XO and AO as competent nitrite reductases are reviewed. The evidence suggesting that these enzymes are probable players of the mammalian NO metabolism is also discussed.
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Affiliation(s)
- Luisa B Maia
- LAQV, REQUIMTE, Department of Chemistry, NOVA School of Science and Technology (FCT NOVA), 2829-516 Caparica, Portugal
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Ortega-Trejo JA, Bobadilla NA. Is Renal Ischemic Preconditioning an Alternative to Ameliorate the Short- and Long-Term Consequences of Acute Kidney Injury? Int J Mol Sci 2023; 24:ijms24098345. [PMID: 37176051 PMCID: PMC10178892 DOI: 10.3390/ijms24098345] [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: 03/14/2023] [Revised: 04/21/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Acute kidney injury (AKI) is a global health problem and has recently been recognized as a risk factor for developing chronic kidney disease (CKD). Unfortunately, there are no effective treatments to reduce or prevent AKI, which results in high morbidity and mortality rates. Ischemic preconditioning (IPC) has emerged as a promising strategy to prevent, to the extent possible, renal tissue from AKI. Several studies have used this strategy, which involves short or long cycles of ischemia/reperfusion (IR) prior to a potential fatal ischemic injury. In most of these studies, IPC was effective at reducing renal damage. Since the first study that showed renoprotection due to IPC, several studies have focused on finding the best strategy to activate correctly and efficiently reparative mechanisms, generating different modalities with promising results. In addition, the studies performing remote IPC, by inducing an ischemic process in distant tissues before a renal IR, are also addressed. Here, we review in detail existing studies on IPC strategies for AKI pathophysiology and the proposed triggering mechanisms that have a positive impact on renal function and structure in animal models of AKI and in humans, as well as the prospects and challenges for its clinical application.
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Affiliation(s)
- Juan Antonio Ortega-Trejo
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Norma A Bobadilla
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
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Xu S, Chuang CY, Malle E, Gamon LF, Hawkins CL, Davies MJ. Influence of plasma halide, pseudohalide and nitrite ions on myeloperoxidase-mediated protein and extracellular matrix damage. Free Radic Biol Med 2022; 188:162-174. [PMID: 35718304 DOI: 10.1016/j.freeradbiomed.2022.06.222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 06/11/2022] [Indexed: 01/15/2023]
Abstract
Myeloperoxidase (MPO) mediates pathogen destruction by generating the bactericidal oxidant hypochlorous acid (HOCl). Formation of this oxidant is however associated with host tissue damage and disease. MPO also utilizes H2O2 to oxidize other substrates, and we hypothesized that mixtures of other plasma anions, including bromide (Br-), iodide (I-), thiocyanate (SCN-) and nitrite (NO2-), at normal or supplemented concentrations, might modulate MPO-mediated HOCl damage. For the (pseudo)halide anions, only SCN- significantly modulated HOCl formation (IC50 ∼33 μM), which is within the normal physiological range, as judged by damage to human plasma fibronectin or extracellular matrix preparations detected by ELISA and LC-MS. NO2- modulated HOCl-mediated damage, in a dose-dependent manner, at physiologically-attainable anion concentrations. However, this was accompanied by increased tyrosine and tryptophan nitration (detected by ELISA and LC-MS), and the overall extent of damage remained approximately constant. Increasing NO2- concentrations (0.5-20 μM) diminished HOCl-mediated modification of tyrosine and methionine, whereas tryptophan loss was enhanced. At higher NO2- concentrations, enhanced tyrosine and methionine loss was detected. These analytical data were confirmed in studies of cell adhesion and metabolic activity. Together, these data indicate that endogenous plasma levels of SCN- (but not Br- or I-) can modulate protein modification induced by MPO, including the extent of chlorination. In contrast, NO2- alters the type of modification, but does not markedly decrease its extent, with chlorination replaced by nitration. These data also indicate that MPO could be a major source of nitration in vivo, and particularly at inflammatory sites where NO2- levels are often elevated.
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Affiliation(s)
- Shuqi Xu
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Denmark
| | - Christine Y Chuang
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Denmark
| | - Ernst Malle
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Luke F Gamon
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Denmark
| | - Clare L Hawkins
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Denmark
| | - Michael J Davies
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Denmark.
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8
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Jeddi S, Gheibi S, Afzali H, Carlström M, Kashfi K, Ghasemi A. Hydrogen sulfide potentiates the protective effects of nitrite against myocardial ischemia-reperfusion injury in type 2 diabetic rats. Nitric Oxide 2022; 124:15-23. [PMID: 35504499 DOI: 10.1016/j.niox.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/06/2022] [Accepted: 04/27/2022] [Indexed: 10/18/2022]
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Bajic Z, Sobot T, Skrbic R, Stojiljkovic MP, Ponorac N, Matavulj A, Djuric DM. Homocysteine, Vitamins B6 and Folic Acid in Experimental Models of Myocardial Infarction and Heart Failure—How Strong Is That Link? Biomolecules 2022; 12:biom12040536. [PMID: 35454125 PMCID: PMC9027107 DOI: 10.3390/biom12040536] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/24/2022] [Accepted: 03/28/2022] [Indexed: 12/29/2022] Open
Abstract
Cardiovascular diseases are the leading cause of death and the main cause of disability. In the last decade, homocysteine has been found to be a risk factor or a marker for cardiovascular diseases, including myocardial infarction (MI) and heart failure (HF). There are indications that vitamin B6 plays a significant role in the process of transsulfuration in homocysteine metabolism, specifically, in a part of the reaction in which homocysteine transfers a sulfhydryl group to serine to form α-ketobutyrate and cysteine. Therefore, an elevated homocysteine concentration (hyperhomocysteinemia) could be a consequence of vitamin B6 and/or folate deficiency. Hyperhomocysteinemia in turn could damage the endothelium and the blood vessel wall and induce worsening of atherosclerotic process, having a negative impact on the mechanisms underlying MI and HF, such as oxidative stress, inflammation, and altered function of gasotransmitters. Given the importance of the vitamin B6 in homocysteine metabolism, in this paper, we review its role in reducing oxidative stress and inflammation, influencing the functions of gasotransmitters, and improving vasodilatation and coronary flow in animal models of MI and HF.
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Affiliation(s)
- Zorislava Bajic
- Department of Physiology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (Z.B.); (T.S.); (N.P.); (A.M.)
| | - Tanja Sobot
- Department of Physiology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (Z.B.); (T.S.); (N.P.); (A.M.)
| | - Ranko Skrbic
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (R.S.); (M.P.S.)
| | - Milos P. Stojiljkovic
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (R.S.); (M.P.S.)
| | - Nenad Ponorac
- Department of Physiology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (Z.B.); (T.S.); (N.P.); (A.M.)
| | - Amela Matavulj
- Department of Physiology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina; (Z.B.); (T.S.); (N.P.); (A.M.)
| | - Dragan M. Djuric
- Faculty of Medicine, Institute of Medical Physiology “Richard Burian”, University of Belgrade, 11000 Belgrade, Serbia
- Correspondence:
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10
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Griffiths K, Lee JJ, Frenneaux MP, Feelisch M, Madhani M. Nitrite and myocardial ischaemia reperfusion injury. Where are we now? Pharmacol Ther 2021; 223:107819. [PMID: 33600852 DOI: 10.1016/j.pharmthera.2021.107819] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
Cardiovascular disease remains the leading cause of death worldwide despite major advances in technology and treatment, with coronary heart disease (CHD) being a key contributor. Following an acute myocardial infarction (AMI), it is imperative that blood flow is rapidly restored to the ischaemic myocardium. However, this restoration is associated with an increased risk of additional complications and further cardiomyocyte death, termed myocardial ischaemia reperfusion injury (IRI). Endogenously produced nitric oxide (NO) plays an important role in protecting the myocardium from IRI. It is well established that NO mediates many of its downstream functions through the 'canonical' NO-sGC-cGMP pathway, which is vital for cardiovascular homeostasis; however, this pathway can become impaired in the face of inadequate delivery of necessary substrates, in particular L-arginine, oxygen and reducing equivalents. Recently, it has been shown that during conditions of ischaemia an alternative pathway for NO generation exists, which has become known as the 'nitrate-nitrite-NO pathway'. This pathway has been reported to improve endothelial dysfunction, protect against myocardial IRI and attenuate infarct size in various experimental models. Furthermore, emerging evidence suggests that nitrite itself provides multi-faceted protection, in an NO-independent fashion, against a myriad of pathophysiologies attributed to IRI. In this review, we explore the existing pre-clinical and clinical evidence for the role of nitrate and nitrite in cardioprotection and discuss the lessons learnt from the clinical trials for nitrite as a perconditioning agent. We also discuss the potential future for nitrite as a pre-conditioning intervention in man.
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Affiliation(s)
- Kayleigh Griffiths
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Jordan J Lee
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Michael P Frenneaux
- Norwich Medical School, University of East Anglia, Bob Champion Research and Education Building, Norwich Research Park, Norwich NR4 7UQ, UK
| | - Martin Feelisch
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Melanie Madhani
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
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11
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Quesnelle K, Guimaraes DA, Rao K, Singh AB, Wang Y, Hogg N, Shiva S. Myoglobin promotes nitrite-dependent mitochondrial S-nitrosation to mediate cytoprotection after hypoxia/reoxygenation. Nitric Oxide 2020; 104-105:36-43. [PMID: 32891753 DOI: 10.1016/j.niox.2020.08.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/15/2020] [Accepted: 08/31/2020] [Indexed: 10/23/2022]
Abstract
It is well established that myoglobin supports mitochondrial respiration through the storage and transport of oxygen as well as through the scavenging of nitric oxide. However, during ischemia/reperfusion (I/R), myoglobin and mitochondria both propagate myocardial injury through the production of oxidants. Nitrite, an endogenous signaling molecule and dietary constituent, mediates potent cardioprotection after I/R and this effect relies on its interaction with both myoglobin and mitochondria. While independent mechanistic studies have demonstrated that nitrite-mediated cardioprotection requires the presence of myoglobin and the post-translational S-nitrosation of critical cysteine residues on mitochondrial complex I, it is unclear whether myoglobin directly catalyzes the S-nitrosation of complex I or whether mitochondrial-dependent nitrite reductase activity contributes to S-nitrosation. Herein, using purified myoglobin and isolated mitochondria, we characterize and directly compare the nitrite reductase activities of mitochondria and myoglobin and assess their contribution to mitochondrial S-nitrosation. We demonstrate that myoglobin is a significantly more efficient nitrite reductase than isolated mitochondria. Further, deoxygenated myoglobin catalyzes the nitrite-dependent S-nitrosation of mitochondrial proteins. This reaction is enhanced in the presence of oxidized (Fe3+) myoglobin and not significantly affected by inhibitors of mitochondrial respiration. Using a Chinese Hamster Ovary cell model stably transfected with human myoglobin, we show that both myoglobin and mitochondrial complex I expression are required for nitrite-dependent attenuation of cell death after anoxia/reoxygenation. These data expand the understanding of myoglobin's role both as a nitrite reductase to a mediator of S-nitrosation and as a regulator of mitochondrial function, and have implications for nitrite-mediated cardioprotection after I/R.
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Affiliation(s)
- Kelly Quesnelle
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Danielle A Guimaraes
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Krithika Rao
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | | | - Yinna Wang
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Neil Hogg
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Sruti Shiva
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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12
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Mohd Faudzi SM, Leong SW, Auwal FA, Abas F, Wai LK, Ahmad S, Tham CL, Shaari K, Lajis NH, Yamin BM. In silico studies, nitric oxide, and cholinesterases inhibition activities of pyrazole and pyrazoline analogs of diarylpentanoids. Arch Pharm (Weinheim) 2020; 354:e2000161. [PMID: 32886410 DOI: 10.1002/ardp.202000161] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/12/2020] [Accepted: 08/14/2020] [Indexed: 11/09/2022]
Abstract
A new series of pyrazole, phenylpyrazole, and pyrazoline analogs of diarylpentanoids (excluding compounds 3a, 4a, 5a, and 5b) was pan-assay interference compounds-filtered and synthesized via the reaction of diarylpentanoids with hydrazine monohydrate and phenylhydrazine. Each analog was evaluated for its anti-inflammatory ability via the suppression of nitric oxide (NO) on IFN-γ/LPS-activated RAW264.7 macrophage cells. The compounds were also investigated for their inhibitory capability toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), using a modification of Ellman's spectrophotometric method. The most potent NO inhibitor was found to be phenylpyrazole analog 4c, followed by 4e, when compared with curcumin. In contrast, pyrazole 3a and pyrazoline 5a were found to be the most selective and effective BChE inhibitors over AChE. The data collected from the single-crystal X-ray diffraction analysis of compound 5a were then applied in a docking simulation to determine the potential binding interactions that were responsible for the anti-BChE activity. The results obtained signify the potential of these pyrazole and pyrazoline scaffolds to be developed as therapeutic agents against inflammatory conditions and Alzheimer's disease.
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Affiliation(s)
- Siti Munirah Mohd Faudzi
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.,Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - S Wei Leong
- Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Faruk A Auwal
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Faridah Abas
- Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.,Department of Food Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Lam K Wai
- Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Syahida Ahmad
- Department of Biochemistry, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Chau L Tham
- Department of Biomedical Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Khozirah Shaari
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.,Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Nordin H Lajis
- Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Bohari M Yamin
- School of Chemical Sciences and Food Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia
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13
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Kapil V, Khambata RS, Jones DA, Rathod K, Primus C, Massimo G, Fukuto JM, Ahluwalia A. The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway. Pharmacol Rev 2020; 72:692-766. [PMID: 32576603 DOI: 10.1124/pr.120.019240] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
In contrast to nitric oxide, which has well established and important roles in the regulation of blood flow and thrombosis, neurotransmission, the normal functioning of the genitourinary system, and the inflammation response and host defense, its oxidized metabolites nitrite and nitrate have, until recently, been considered to be relatively inactive. However, this view has been radically revised over the past decade and more. Much evidence has now accumulated demonstrating that nitrite serves as a storage form of nitric oxide, releasing nitric oxide preferentially under acidic and/or hypoxic conditions but also occurring under physiologic conditions: a phenomenon that is catalyzed by a number of distinct mammalian nitrite reductases. Importantly, preclinical studies demonstrate that reduction of nitrite to nitric oxide results in a number of beneficial effects, including vasodilatation of blood vessels and lowering of blood pressure, as well as cytoprotective effects that limit the extent of damage caused by an ischemia/reperfusion insult, with this latter issue having been translated more recently to the clinical setting. In addition, research has demonstrated that the other main metabolite of the oxidation of nitric oxide (i.e., nitrate) can also be sequentially reduced through processing in vivo to nitrite and then nitrite to nitric oxide to exert a range of beneficial effects-most notably lowering of blood pressure, a phenomenon that has also been confirmed recently to be an effective method for blood pressure lowering in patients with hypertension. This review will provide a detailed description of the pathways involved in the bioactivation of both nitrate and nitrite in vivo, their functional effects in preclinical models, and their mechanisms of action, as well as a discussion of translational exploration of this pathway in diverse disease states characterized by deficiencies in bioavailable nitric oxide. SIGNIFICANCE STATEMENT: The past 15 years has seen a major revision in our understanding of the pathways for nitric oxide synthesis in the body with the discovery of the noncanonical pathway for nitric oxide generation known as the nitrate-nitrite-nitric oxide pathway. This review describes the molecular components of this pathway, its role in physiology, potential therapeutics of targeting this pathway, and their impact in experimental models, as well as the clinical translation (past and future) and potential side effects.
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Affiliation(s)
- V Kapil
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - R S Khambata
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - D A Jones
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - K Rathod
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - C Primus
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - G Massimo
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - J M Fukuto
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
| | - A Ahluwalia
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.)
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14
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Yu GZ, Istvanic F, Chen X, Nouraie M, Shiva S, Straub AC, Pacella JJ. Ultrasound-Targeted Microbubble Cavitation with Sodium Nitrite Synergistically Enhances Nitric Oxide Production and Microvascular Perfusion. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:667-678. [PMID: 31810801 PMCID: PMC7010556 DOI: 10.1016/j.ultrasmedbio.2019.10.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/16/2019] [Accepted: 10/16/2019] [Indexed: 06/10/2023]
Abstract
Microvascular obstruction is a common repercussion of percutaneous coronary intervention for distal microembolization, ischemia-reperfusion injury and inflammation, which increases post-myocardial infarction heart failure and mortality. Ultrasound-targeted microbubble cavitation (UTMC) may resolve microvascular obstruction while activating endothelial nitric oxide synthase (eNOS) and increasing endothelium-derived nitric oxide (NO) bioavailability. Nitrite, a cardioprotective agent, offers an additional source of NO and potential synergy with UTMC. UTMC and nitrite co-therapy increased microvascular perfusion and NO concentration in a rat hindlimb model. Using N-nitro-L-arginine methyl ester for eNOS blockade, we found a three-way interaction effect between nitrite, UTMC and eNOS on microvascular perfusion and NO production. Modulating ultrasound peak negative acoustic pressure (0.33-1.5 MPa) significantly affected outcomes, while microbubble dosage (2 × 108 bubbles/mL, 1.5 mL/h to 1 × 109 bubbles/mL, 3 mL/h) did not. Nitrite co-therapy also protected against oxidative stress. Comparison of nitrite to sodium nitroprusside with UTMC revealed synergistic effects were specific to nitrite. Synergy between UTMC and nitrite holds therapeutic potential for cardiovascular disease.
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Affiliation(s)
- Gary Z Yu
- Center for Ultrasound and Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Filip Istvanic
- Center for Ultrasound and Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Xucai Chen
- Center for Ultrasound and Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mehdi Nouraie
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sruti Shiva
- Vascular Medicine Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Adam C Straub
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - John J Pacella
- Center for Ultrasound and Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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15
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Rochon ER, Missinato MA, Xue J, Tejero J, Tsang M, Gladwin MT, Corti P. Nitrite Improves Heart Regeneration in Zebrafish. Antioxid Redox Signal 2020; 32:363-377. [PMID: 31724431 PMCID: PMC6985782 DOI: 10.1089/ars.2018.7687] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Aims: Nitrite is reduced to nitric oxide (NO) under physiological and pathological hypoxic conditions to modulate angiogenesis and improve ischemia-reperfusion injury. Although adult mammals lack the ability to regenerate the heart after injury, this is preserved in neonates and efforts to reactivate this process are of great interest. Unlike mammals, the adult zebrafish maintain the innate ability to regenerate their hearts after injury, providing an important model to study cardiac regeneration. We thus explored the effects of physiological levels of nitrite on cardiac and fin regeneration and downstream cellular and molecular signaling pathways in response to amputation and cryoinjury. Results: Nitrite treatment of zebrafish after ventricular amputation or cryoinjury to the heart in hypoxic water (∼3 parts per million of oxygen) increases cardiomyocyte proliferation, improves angiogenesis, and enhances early recruitment of thrombocytes, macrophages, and neutrophils to the injury. When tested in a fin regeneration model, neutrophil recruitment to the injury site was found to be dependent on NO. Innovation: This is the first study to evaluate effects of physiological levels of nitrite on cardiac regeneration in response to cardiac injury, with the observation that nitrite in water accelerates zebrafish heart regeneration. Conclusion: Physiological and therapeutic levels of nitrite increase thrombocyte, neutrophil, and macrophage recruitment to the heart after amputation and cryoinjury in zebrafish, resulting in accelerated cardiomyocyte proliferation and angiogenesis. Translation of this finding to mammalian models of injury during early development may provide an opportunity to improve outcomes during intrauterine fetal or neonatal cardiac surgery.
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Affiliation(s)
- Elizabeth R Rochon
- Department of Medicine, Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Jianmin Xue
- Department of Medicine, Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jesús Tejero
- Department of Medicine, Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.,Division of Pulmonary, Department of Medicine, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael Tsang
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mark T Gladwin
- Department of Medicine, Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.,Division of Pulmonary, Department of Medicine, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Paola Corti
- Department of Medicine, Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.,Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.,Ri.MED Foundation, Palermo, Italy
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16
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Rochon ER, Corti P. Globins and nitric oxide homeostasis in fish embryonic development. Mar Genomics 2020; 49:100721. [PMID: 31711848 DOI: 10.1016/j.margen.2019.100721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/07/2019] [Accepted: 10/18/2019] [Indexed: 11/30/2022]
Abstract
Since the discovery of new members of the globin superfamily such as Cytoglobin, Neuroglobin and Globin X, in addition to the most well-known members, Hemoglobin and Myoglobin, different hypotheses have been suggested about their function in vertebrates. Globins are ubiquitously found in living organisms and can carry out different functions based on their ability to bind ligands such as O2, and nitric oxide (NO) and to catalyze reactions scavenging NO or generating NO by reducing nitrite. NO is a highly diffusible molecule with a central role in signaling important for egg maturation, fertilization and early embryonic development. The globins ability to scavenge or generate NO makes these proteins ideal candidates in regulating NO homeostasis depending on the micro environment and tissue NO demands. Different amounts of various globins have been found in zebrafish eggs and developing embryos where it's unlikely that they function as respiratory proteins and instead could play a role in maintaining embryonic NO homeostasis. Here we summarize the current knowledge concerning the role of NO in adult fish in comparison to mammals and we discuss NO function during embryonic development with possible implications for globins in maintaining embryonic NO homeostasis.
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Affiliation(s)
- Elizabeth R Rochon
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Paola Corti
- Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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17
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Liu Y, Croft KD, Hodgson JM, Mori T, Ward NC. Mechanisms of the protective effects of nitrate and nitrite in cardiovascular and metabolic diseases. Nitric Oxide 2020; 96:35-43. [PMID: 31954804 DOI: 10.1016/j.niox.2020.01.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/18/2019] [Accepted: 01/13/2020] [Indexed: 12/28/2022]
Abstract
Within the body, NO is produced by nitric oxide synthases via converting l-arginine to citrulline. Additionally, NO is also produced via the NOS-independent nitrate-nitrite-NO pathway. Unlike the classical pathway, the nitrate-nitrite-NO pathway is oxygen independent and viewed as a back-up function to ensure NO generation during ischaemia/hypoxia. Dietary nitrate and nitrite have emerged as substrates for endogenous NO generation and other bioactive nitrogen oxides with promising protective effects on cardiovascular and metabolic function. In brief, inorganic nitrate and nitrite can decrease blood pressure, protect against ischaemia-reperfusion injury, enhance endothelial function, inhibit platelet aggregation, modulate mitochondrial function and improve features of the metabolic syndrome. However, many questions regarding the specific mechanisms of these protective effects on cardiovascular and metabolic diseases remain unclear. In this review, we focus on nitrate/nitrite bioactivation, as well as the potential mechanisms for nitrate/nitrite-mediated effects on cardiovascular and metabolic diseases. Understanding how dietary nitrate and nitrite induce beneficial effect on cardiovascular and metabolic diseases could open up novel therapeutic opportunities in clinical practice.
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Affiliation(s)
- Yang Liu
- School of Biomedical Sciences, University of Western Australia, Perth, Australia
| | - Kevin D Croft
- School of Biomedical Sciences, University of Western Australia, Perth, Australia
| | - Jonathan M Hodgson
- School of Biomedical Sciences, University of Western Australia, Perth, Australia; School of Medical and Health Sciences, Edith Cowan University, Perth, Australia
| | - Trevor Mori
- Medical School, University of Western Australia, Perth, Australia
| | - Natalie C Ward
- Medical School, University of Western Australia, Perth, Australia; School of Public Health and Curtin Health Innovation Research Institute, Curtin University, Perth, Australia.
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18
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Lambden S. Bench to bedside review: therapeutic modulation of nitric oxide in sepsis-an update. Intensive Care Med Exp 2019; 7:64. [PMID: 31792745 PMCID: PMC6888802 DOI: 10.1186/s40635-019-0274-x] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 10/11/2019] [Indexed: 12/17/2022] Open
Abstract
Nitric oxide is a signalling molecule with an extensive range of functions in both health and disease. Discovered in the 1980s through work that earned the Nobel prize, nitric oxide is an essential factor in regulating cardiovascular, immune, neurological and haematological function in normal homeostasis and in response to infection. Early work implicated exaggerated nitric oxide synthesis as a potentially important driver of septic shock; however, attempts to modulate production through global inhibition of nitric oxide synthase were associated with increased mortality. Subsequent work has shown that regulation of nitric oxide production is determined by numerous factors including substrate and co-factor availability and expression of endogenous regulators. In sepsis, nitric oxide synthesis is dysregulated with exaggerated production leading to cardiovascular dysfunction, bioenergetic failure and cellular toxicity whilst at the same time impaired microvascular function may be driven in part by reduced nitric oxide synthesis by the endothelium. This bench to bedside review summarises our current understanding of the ways in which nitric oxide production is regulated on a tissue and cellular level before discussing progress in translating these observations into novel therapeutic strategies for patients with sepsis.
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Affiliation(s)
- Simon Lambden
- Department of Medicine, Addenbrooke's Hospital, Cambridge University, 5th Floor, Cambridge, CB20QQ, UK.
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19
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Uray T, Empey PE, Drabek T, Stezoski JP, Janesko-Feldman K, Jackson T, Garman RH, Kim F, Kochanek PM, Dezfulian C. Nitrite pharmacokinetics, safety and efficacy after experimental ventricular fibrillation cardiac arrest. Nitric Oxide 2019; 93:71-77. [PMID: 31526855 PMCID: PMC6957908 DOI: 10.1016/j.niox.2019.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 07/12/2019] [Accepted: 09/10/2019] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Besides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA. However, little is known about brain penetration or pharmacokinetics (PK). Therefore, to define the optimal use of this agent, studies on the PK of nitrite in experimental ventricular fibrillation (VF) are needed. We tested the hypothesis that nitrite administered after resuscitation from VF is detectable in cerebrospinal fluid (CSF), brain and other organ tissues, produces no adverse hemodynamic effects, and improves neurologic outcome in rats. METHODS After return of spontaneous circulation (ROSC) of 5 min untreated VF, adult male Sprague-Dawley rats were given intravenous nitrite (8 μM, 0.13 mg/kg) or placebo as a 5 min infusion beginning at 5 min after CA. Additionally, sham groups with and without nitrite treatment were also studied. Whole blood nitrite levels were serially measured. After 15 min, CSF, brain, heart and liver tissue were collected. In a second series, using a randomized and blinded treatment protocol, rats were treated with nitrite or placebo after arrest. Neurological deficit scoring (NDS) was performed daily and eight days after resuscitation, fear conditioning testing (FCT) and brain histology were assessed. RESULTS In an initial series of experiments, rats (n = 21) were randomized to 4 groups: VF-CPR and nitrite therapy (n = 6), VF-CPR and placebo therapy (n = 5), sham (n = 5), or sham plus nitrite therapy (n = 5). Whole blood nitrite levels increased during drug infusion to 57.14 ± 10.82 μM at 11 min post-resuscitation time (1 min after dose completion) in the VF nitrite group vs. 0.94 ± 0.58 μM in the VF placebo group (p < 0.001). There was a significant difference between the treatment and placebo groups in nitrite levels in blood between 7.5 and 15 min after CPR start and between groups with respect to nitrite levels in CSF, brain, heart and liver. In a second series (n = 25 including 5 shams), 19 out of 20 animals survived until day 8. However, NDS, FCT and brain histology did not show any statistically significant difference between groups. CONCLUSIONS Nitrite, administered early after ROSC from VF, was shown to cross the blood brain barrier after a 5 min VF cardiac arrest. We characterized the PK of intravenous nitrite administration after VF and were able to demonstrate nitrite safety in this feasibility study.
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Affiliation(s)
- Thomas Uray
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, PA, USA; Department of Emergency Medicine, Medical University of Vienna, Austria
| | - Philip E Empey
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, PA, USA; Department of Pharmacy and Therapeutics, University of Pittsburgh, PA, USA
| | - Tomas Drabek
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, PA, USA; Department of Anesthesiology, University of Pittsburgh School of Medicine, PA, USA
| | - Jason P Stezoski
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, PA, USA
| | - Keri Janesko-Feldman
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, PA, USA
| | - Travis Jackson
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, PA, USA
| | - Robert H Garman
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Francis Kim
- Department of Medicine, Harborview Medical Center, University of Washington, Seattle, WA, USA
| | - Patrick M Kochanek
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, PA, USA
| | - Cameron Dezfulian
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, PA, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
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20
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Kwak HJ, Um JY, Lee SS. Mild NO preconditioning protects H9c2 cells against NO-induced apoptosis through activation of PI3K/Akt and PKA-dependent pathways. Mol Cell Toxicol 2019. [DOI: 10.1007/s13273-019-0033-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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21
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Kobayashi J, Murata I. Nitrite as a pharmacological intervention for the successful treatment of crush syndrome. Physiol Rep 2019; 6. [PMID: 29512311 PMCID: PMC5840435 DOI: 10.14814/phy2.13633] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 01/16/2018] [Accepted: 02/02/2018] [Indexed: 01/01/2023] Open
Abstract
Crush syndrome is characterized by ischemia/reperfusion injury (IRI). The protective effect of nitrite on experimentally induced IRI has been demonstrated in the heart, kidney, liver, and skeletal muscle. IRI in tissues and systemic organs occurs due to the massive generation of reactive oxygen species and subsequent systemic inflammation. Therefore, ischemic pre and postconditioning are performed in clinical practice. Intravenous administration of nitrite inhibits IRI through nitric oxide-mediated mechanisms. In this paper, we discuss the utility of nitrite as a pharmacological postconditioning agent in the treatment of crush syndrome.
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Affiliation(s)
- Jun Kobayashi
- Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmacy and Pharmaceutical Science, Josai University, Saitama, Japan
| | - Isamu Murata
- Division of Drug Safety Management, Faculty of Pharmacy and Pharmaceutical Science, Josai University, Saitama, Japan
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22
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Tejero J, Shiva S, Gladwin MT. Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation. Physiol Rev 2019; 99:311-379. [PMID: 30379623 PMCID: PMC6442925 DOI: 10.1152/physrev.00036.2017] [Citation(s) in RCA: 338] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 03/30/2018] [Accepted: 05/06/2018] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) is a small free radical with critical signaling roles in physiology and pathophysiology. The generation of sufficient NO levels to regulate the resistance of the blood vessels and hence the maintenance of adequate blood flow is critical to the healthy performance of the vasculature. A novel paradigm indicates that classical NO synthesis by dedicated NO synthases is supplemented by nitrite reduction pathways under hypoxia. At the same time, reactive oxygen species (ROS), which include superoxide and hydrogen peroxide, are produced in the vascular system for signaling purposes, as effectors of the immune response, or as byproducts of cellular metabolism. NO and ROS can be generated by distinct enzymes or by the same enzyme through alternate reduction and oxidation processes. The latter oxidoreductase systems include NO synthases, molybdopterin enzymes, and hemoglobins, which can form superoxide by reduction of molecular oxygen or NO by reduction of inorganic nitrite. Enzymatic uncoupling, changes in oxygen tension, and the concentration of coenzymes and reductants can modulate the NO/ROS production from these oxidoreductases and determine the redox balance in health and disease. The dysregulation of the mechanisms involved in the generation of NO and ROS is an important cause of cardiovascular disease and target for therapy. In this review we will present the biology of NO and ROS in the cardiovascular system, with special emphasis on their routes of formation and regulation, as well as the therapeutic challenges and opportunities for the management of NO and ROS in cardiovascular disease.
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Affiliation(s)
- Jesús Tejero
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania ; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania ; Department of Pharmacology and Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Sruti Shiva
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania ; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania ; Department of Pharmacology and Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Mark T Gladwin
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania ; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania ; Department of Pharmacology and Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
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Maia LB, Moura JJG. Putting xanthine oxidoreductase and aldehyde oxidase on the NO metabolism map: Nitrite reduction by molybdoenzymes. Redox Biol 2018; 19:274-289. [PMID: 30196191 PMCID: PMC6129670 DOI: 10.1016/j.redox.2018.08.020] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 08/23/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide radical (NO) is a signaling molecule involved in several physiological and pathological processes and a new nitrate-nitrite-NO pathway has emerged as a physiological alternative to the "classic" pathway of NO formation from L-arginine. Since the late 1990s, it has become clear that nitrite can be reduced back to NO under hypoxic/anoxic conditions and exert a significant cytoprotective action in vivo under challenging conditions. To reduce nitrite to NO, mammalian cells can use different metalloproteins that are present in cells to perform other functions, including several heme proteins and molybdoenzymes, comprising what we denominated as the "non-dedicated nitrite reductases". Herein, we will review the current knowledge on two of those "non-dedicated nitrite reductases", the molybdoenzymes xanthine oxidoreductase and aldehyde oxidase, discussing the in vitro and in vivo studies to provide the current picture of the role of these enzymes on the NO metabolism in humans.
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Affiliation(s)
- Luisa B Maia
- LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.
| | - José J G Moura
- LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
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Parviz Y, Waleed M, Vijayan S, Adlam D, Lavi S, Al Nooryani A, Iqbal J, Stone GW. Cellular and molecular approaches to enhance myocardial recovery after myocardial infarction. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2018; 20:351-364. [PMID: 29958820 DOI: 10.1016/j.carrev.2018.05.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 05/22/2018] [Accepted: 05/29/2018] [Indexed: 10/14/2022]
Abstract
Reperfusion therapy has resulted in significant improvement in post-myocardial infarction morbidity and mortality in over the last 4 decades. Nonetheless, it is well recognized that simply restoring patency of the epicardial artery may not stop or reverse damage at microvascular level, and myocardial salvage is often suboptimal. Numerous efforts have been undertaken to elucidate the mechanisms underlying extensive myonecrosis to facilitate the discovery of therapies to provide additional and incremental benefits over current therapeutic pathways. To date, conclusively effective strategies to promote myocardial recovery have not yet been established. Novel approaches are investigating the foundational cellular and molecular bases of myocardial ischemia and irreversible injury. Herein, we review the emerging concepts and proposed therapies that may improve myocardial protection and reduce infarct size. We examine the preclinical and clinical evidence for reduced infarct size with these strategies, including anti-inflammatory agents, intracellular ion channel modulators, agents affecting the reperfusion injury salvage kinase (RISK) and nitric oxide signaling pathways, modulators of mitochondrial function, anti-apoptotic agents, and stem cell and gene therapy. We review the potential reasons of failures to date and the potential for new strategies to further promote myocardial recovery and improve prognosis.
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Affiliation(s)
- Yasir Parviz
- New York Presbyterian Hospital, Columbia University Medical Centre and the Cardiovascular Research Foundation, New York, NY, USA.
| | | | | | - David Adlam
- Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, UK
| | - Shahar Lavi
- Division of Cardiology, London Health Sciences Centre, Western University, London, Ontario, Canada
| | | | - Javaid Iqbal
- South Yorkshire Cardiothoracic Centre, Northern General Hospital, Sheffield, UK
| | - Gregg W Stone
- New York Presbyterian Hospital, Columbia University Medical Centre and the Cardiovascular Research Foundation, New York, NY, USA
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Low-Dose Sodium Nitrite Fluid Resuscitation Prevents Lethality From Crush Syndrome by Improving Nitric Oxide Consumption and Preventing Myoglobin Cytotoxicity in Kidney in A Rat Model. Shock 2018; 48:112-118. [PMID: 27941593 DOI: 10.1097/shk.0000000000000817] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE Crush syndrome (CS) is a serious medical condition characterized by muscle cell damage resulting from pressure. CS has a high mortality, even when patients receive fluid therapy. We examined whether administration of NaNO2-containing fluid can improve survival in a rat model of CS. DESIGN The CS model was generated by subjecting anesthetized rats to bilateral hind limb compression with a rubber tourniquet for 5 h. Rats were then randomly divided into six groups: sham; CS with no treatment; CS with normal saline treatment; CS with normal saline + 25 mEq/L bicarbonate treatment; and CS with normal saline + 200 or 500 μmol/kg NaNO2. MEASUREMENTS AND MAIN RESULTS Blood and tissue samples were collected for histological and biochemical analyses at predetermined time points before and after reperfusion. Ischemic compression of rat hind limbs reduced nitrite content in the crushed muscle, and subsequent reperfusion resulted in reactive oxygen species-induced circulatory dysfunction and systemic inflammation. Rats treated with 200 μmol/kg NaNO2 showed increased nitric oxide (NO) levels, blood circulation, and neoangiogenesis, decreased generation of reactive oxygen species, and suppression of the inflammatory response, leading to complete recovery. CONCLUSIONS Treatment with 200 μmol/kg NaNO2 prevents muscle damage induced by ischemia reperfusion via the protective effects of NO and suppression of systemic inflammation, thereby increasing survival rates in CS.
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Abstract
BACKGROUND Nitrite has been shown to reduce right ventricle (RV) remodeling in experimental pulmonary hypertension. However, whether this effect is due to a reduction in RV afterload (ie, reduction in pulmonary artery pressure) or a direct effect on the RV itself remains unanswered. We hypothesize that nitrite has direct effects on RV remodeling and studied its effects in mice with pulmonary artery banding (PAB). METHODS AND RESULTS PAB decreased exercise tolerance and reduced RV systolic and diastolic function. Nitrite treatment attenuated the decrease in RV systolic function and improved the RV diastolic function. Nitrite-treated mice with PAB had similar exercise tolerance compared with a control group. PAB induced RV hypertrophy and fibrosis which were associated with increased expression of phospho-Akt. Interestingly, nitrite treatment attenuated PAB-induced RV hypertrophy and reduced the expression of phospho-Akt in RV tissue from mice with PAB. In neonatal rat cardiac fibroblast, nitrite also attenuated hypoxia-induced increase in expression of phospho-Akt. CONCLUSION Our study indicates that nitrite treatment has direct beneficial effects on RV and improves function and attenuates remodeling in RV exposed to chronic pressure overload. These beneficial effects, at least in part, could be due to the inhibition of the phospho-Akt (p-Akt) pathway activation.
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Dezfulian C, Olsufka M, Fly D, Scruggs S, Do R, Maynard C, Nichol G, Kim F. Hemodynamic effects of IV sodium nitrite in hospitalized comatose survivors of out of hospital cardiac arrest. Resuscitation 2017; 122:106-112. [PMID: 29175357 DOI: 10.1016/j.resuscitation.2017.11.055] [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: 08/01/2017] [Revised: 11/08/2017] [Accepted: 11/22/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND Patients resuscitated from cardiac arrest have brain and cardiac injury. Recent animal studies suggest that the administration of sodium nitrite after resuscitation from 12min of asystole limits acute cardiac dysfunction and improves survival and neurologic outcomes. It has been hypothesized that low doses of IV sodium nitrite given during resuscitation of out of hospital cardiac arrest (OHCA) will improve survival. Low doses of sodium nitrite (e.g., 9.6mg of sodium nitrite) are safe in healthy individuals, however the effect of nitrite on blood pressure in resuscitated cardiac arrest patients is unknown. METHODS We performed a single-center, pilot trial of low dose sodium nitrite (1 or 9.6mg dose) vs. placebo in hospitalized out-of-hospital cardiac arrest patient to determine whether nitrite administration reduced blood pressure and whether whole blood nitrite levels increased in response to nitrite administration. RESULTS This is the first reported study of sodium nitrite in cardiac arrest patients. Infusion of low doses of sodium nitrite in comatose survivors of OHCA (n=7) compared to placebo (n=4) had no significant effects on heart rate within 30min after infusion (70±20 vs. 78±3 beats per minute, p=0.18), systolic blood pressure (103±20 vs 108±15mmHg, p=0.3), or methemoglobin levels (0.92±0.33 vs. 0.70±0.26, p=0.45). Serum nitrite levels of 2-4μM were achieved within 15min of a 9.6mg nitrite infusion. CONCLUSIONS Low dose sodium nitrite does not cause significant hemodynamic effect in patients with OHCA, which suggests that nitrite can be delivered safely in this critically ill patient population. Higher doses of sodium nitrite are necessary in order to achieve target serum level of 10μM.
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Affiliation(s)
- Cameron Dezfulian
- Department of Adult and Pediatric Critical Care Medicine, Safar Center for Resuscitation Research and Vascular Medicine Institute, University of Pittsburgh, United States
| | - Michele Olsufka
- Department of Medicine, Harborview Medical Center, University of Washington, United States
| | - Deborah Fly
- Department of Medicine, Harborview Medical Center, University of Washington, United States
| | - Sue Scruggs
- Department of Medicine, Harborview Medical Center, University of Washington, United States
| | - Rose Do
- Department of Medicine, Harborview Medical Center, University of Washington, United States
| | - Charles Maynard
- Department of Health Services, University of Washington, United States
| | - Graham Nichol
- Department of Medicine, Harborview Medical Center, University of Washington, United States
| | - Francis Kim
- Department of Medicine, Harborview Medical Center, University of Washington, United States.
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Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses. J Anesth 2017; 31:885-894. [PMID: 29063286 DOI: 10.1007/s00540-017-2417-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 10/10/2017] [Indexed: 12/12/2022]
Abstract
PURPOSE A specific therapeutic strategy in sepsis-induced myocardial dysfunction remains to be determined. Nitrite may have cardioprotective effects against sepsis-induced myocardial dysfunction. This study investigated the cardioprotective effects of nitrite on myocardial function, mitochondrial bioenergetics, and its underlying molecular mechanisms in severe septic rats. METHODS Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered normal saline (NS group) or nitrite (nitrite group) subcutaneously. We administered nitrite at different doses (0.1-10 mg/kg) to ascertain the most effective dose and examined cardiac function in an isolated heart experiment 8 h after CLP. We investigated mitochondrial bioenergetics and molecular mechanisms underlying the administration of nitrite in vitro. RESULTS In isolated heart experiments, the left ventricular developed pressure (96 ± 5 mmHg) at a moderate nitrite dose (1.0 mg/kg) was significantly higher than that in the NS group (75 ± 4 mmHg, P < 0.05). Mitochondrial oxidative phosphorylation in the nitrite group was significantly higher than that in the NS group (P < 0.01). Immunoblotting revealed that nitrite significantly increased the phosphorylation of Akt (P < 0.05) and reduced the nuclear translocation of NF-κB (P < 0.05) compared with the NS group. Nitrite was also shown to improve the rate of survival in severe septic rats (P < 0.001). CONCLUSIONS Our results showed that a moderate nitrite dose improved septic myocardial dysfunction at organ, cellular, and molecular levels via modulation of stress signal responses, which resulted in an improvement in survival.
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Jeddi S, Khalifi S, Ghanbari M, Bageripour F, Ghasemi A. Effects of Nitrate Intake on Myocardial Ischemia-Reperfusion Injury in Diabetic Rats. Arq Bras Cardiol 2017; 107:339-347. [PMID: 27849257 PMCID: PMC5102480 DOI: 10.5935/abc.20160137] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 03/21/2016] [Indexed: 01/15/2023] Open
Abstract
Background Coronary artery disease is 2-3 times more common in diabetic individuals.
Dietary nitrate/nitrite has beneficial effects in both diabetes and
cardiovascular disease. It also has protective effects against myocardial
ischemia-reperfusion (IR) injury in healthy animals. However, the effects of
nitrate on myocardial IR injury in diabetic rats have not yet been
investigated. Objective We examined the effects of dietary nitrate on myocardial IR injury in
streptozotocin-nicotinamide-induced diabetic rats. Method Rats were divided into four groups (n=7 in each group): control,
control+nitrate, diabetes, and diabetes+nitrate. Type 2 diabetes was induced
by injection of streptozotocin and nicotinamide. Nitrate (sodium nitrate)
was added to drinking water (100 mg/L) for 2 months. The hearts were
perfused in a Langendorff apparatus at 2 months and assessed before
(baseline) and after myocardial IR for the following parameters: left
ventricular developed pressure (LVDP), minimum and maximum rates of pressure
change in the left ventricle (±dP/dt), endothelial nitric oxide (NO)
synthase (eNOS) and inducible NO synthase (iNOS) mRNA expression, and levels
of malondialdehyde (MDA) and NO metabolites (NOx). Results Recovery of LVDP and ±dP/dt was lower in diabetic rats versus
controls, but almost normalized after nitrate intake. Diabetic rats had
lower eNOS and higher iNOS expression both at baseline and after IR, and
dietary nitrate restored these parameters to normal values after IR.
Compared with controls, heart NOx level was lower in diabetic rats at
baseline but was higher after IR. Diabetic rats had higher MDA levels both
at baseline and after IR, which along with heart NOx levels decreased
following nitrate intake. Conclusion Dietary nitrate in diabetic rats provides cardioprotection against IR injury
by regulating eNOS and iNOS expression and inhibiting lipid peroxidation in
the heart.
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Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeedeh Khalifi
- Department of Medical Laboratory Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahboubeh Ghanbari
- Endocrine Physiology Research Center and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Bageripour
- Endocrine Physiology Research Center and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asghar Ghasemi
- Endocrine Physiology Research Center and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Ormerod JOM, Evans JDW, Contractor H, Beretta M, Arif S, Fernandez BO, Feelisch M, Mayer B, Kharbanda RK, Frenneaux MP, Ashrafian H. Human Second Window Pre-Conditioning and Post-Conditioning by Nitrite Is Influenced by a Common Polymorphism in Mitochondrial Aldehyde Dehydrogenase. JACC Basic Transl Sci 2017; 2:13-21. [PMID: 28280793 PMCID: PMC5329169 DOI: 10.1016/j.jacbts.2016.11.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 10/03/2016] [Accepted: 11/04/2016] [Indexed: 01/13/2023]
Abstract
Pre-conditioning is an exciting physiological phenomenon that, despite great efforts, has so far resisted translation to mainstream clinical medicine. Many potential triggers (e.g., ischemia of the organ in question or a remote organ, many different drugs) have been investigated, but recent work has implicated activation of mitochondrial aldehyde dehydrogenase (ALDH2) as central to the process. A genetic polymorphism, known as ALDH2*2, is common worldwide (present in up to 40% of Han Chinese people) and produces a functionally different enzyme. The authors used a variety of protocols in the human ischemic forearm model, in participants with both enzyme types, to assess cytoprotection with low-dose sodium nitrite and attempt to further elucidate the role of ALDH2.
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Affiliation(s)
- Julian O M Ormerod
- Oxford Heart Centre, Oxford University Hospitals, Oxford, United Kingdom
| | - Jonathan D W Evans
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| | - Hussain Contractor
- Department of Cardiovascular Medicine, West Wing, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Matteo Beretta
- Department of Pharmacology and Toxicology, Karl-Franzens-Universität, Graz, Austria
| | - Sayqa Arif
- Department of Cardiovascular Medicine, Medical School, University of Birmingham, Birmingham, United Kingdom
| | - Bernadette O Fernandez
- Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
| | - Martin Feelisch
- Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
| | - Bernd Mayer
- Department of Pharmacology and Toxicology, Karl-Franzens-Universität, Graz, Austria
| | - Rajesh K Kharbanda
- Oxford Heart Centre, Oxford University Hospitals, Oxford, United Kingdom
| | | | - Houman Ashrafian
- Department of Cardiovascular Medicine, West Wing, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
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Khatri J, Mills CE, Maskell P, Odongerel C, Webb AJ. It is rocket science - why dietary nitrate is hard to 'beet'! Part I: twists and turns in the realization of the nitrate-nitrite-NO pathway. Br J Clin Pharmacol 2017; 83:129-139. [PMID: 26896747 PMCID: PMC5338143 DOI: 10.1111/bcp.12913] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 02/17/2016] [Indexed: 12/20/2022] Open
Abstract
Dietary nitrate (found in green leafy vegetables, such as rocket, and in beetroot) is now recognized to be an important source of nitric oxide (NO), via the nitrate-nitrite-NO pathway. Dietary nitrate confers several cardiovascular beneficial effects on blood pressure, platelets, endothelial function, mitochondrial efficiency and exercise. While this pathway may now seem obvious, its realization followed a rather tortuous course over two decades. Early steps included the discovery that nitrite was a source of NO in the ischaemic heart but this appeared to have deleterious effects. In addition, nitrate-derived nitrite provided a gastric source of NO. However, residual nitrite was not thought to be absorbed systemically. Nitrite was also considered to be physiologically inert but potentially carcinogenic, through N-nitrosamine formation. In Part 1 of a two-part Review on the nitrate-nitrite-NO pathway we describe key twists and turns in the elucidation of the pathway and the underlying mechanisms. This provides the critical foundation for the more recent developments in the nitrate-nitrite-NO pathway which are covered in Part 2.
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Affiliation(s)
- Jibran Khatri
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical PharmacologySt. Thomas, HospitalLondonSE1 7EHUK
| | - Charlotte Elizabeth Mills
- Department of Dietetics and Nutrition, Division of Diabetes and Nutritional SciencesKing's College LondonLondonSE1 0NHUK
| | - Perry Maskell
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical PharmacologySt. Thomas, HospitalLondonSE1 7EHUK
| | - Chimed Odongerel
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical PharmacologySt. Thomas, HospitalLondonSE1 7EHUK
| | - Andrew James Webb
- King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical PharmacologySt. Thomas, HospitalLondonSE1 7EHUK
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Jones DA, Rathod KS, Ahluwalia A. Update on Nitrite Reduction in Ischemic Disease: Mechanisms and Clinical Translation. NITRIC OXIDE 2017:195-211. [DOI: 10.1016/b978-0-12-804273-1.00015-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Mirmiran P, Bahadoran Z, Golzarand M, Asghari G, Azizi F. Consumption of nitrate containing vegetables and the risk of chronic kidney disease: Tehran Lipid and Glucose Study. Ren Fail 2016; 38:937-44. [PMID: 27055566 DOI: 10.3109/0886022x.2016.1165118] [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] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND There is growing evidence regarding the potential properties of nitrate-rich foods in development of chronic diseases. In this study, we investigated the association of nitrate-containing vegetables (NCVs) and the risk of chronic kidney disease (CKD). METHODS We evaluated 1546 eligible adult participants of the Tehran Lipid and Glucose Study (TLGS), at baseline (2006-2008) and again after 3 years (2009-2011). Dietary intake was collected using the validated semi-quantitative food frequency questionnaire. Nitrate-containing vegetables and its categories including high-, medium-, and low-nitrate vegetables were defined. Estimated glomerular filtration rate (eGFR) and CKD were defined. Association between NCVs and CKD in the cross-sectional phase and the predictability of NCVs consumption in CKD occurrence were assessed using multivariable logistic regression models with adjustment for potential confounders. RESULTS Mean dietary intake of energy-adjusted NCVs was 298.0 ± 177.3 g/day. Highest compared to the lowest tertile of NCVs was accompanied with a significantly lower mean eGFR (76.6 vs. 83.3, mL/min/1.73 m(2), p < 0.001) and a higher prevalence of CKD (21.7 vs. 9.9%, p < 0.001). At baseline, higher intake of high-NCVs was associated with a 48% higher chance of having CKD (OR = 1.48, 95% CI = 1.05-2.13). After 3 years of follow-up, there was no significant association between consumption of total NCVs and its categories with the occurrence of CKD. CONCLUSION Considering the lack of association between high-NCVs intakes and the risk of CKD in prospective analysis, additional research is recommended to clarify possible effect of nitrate intakes from vegetables on kidney function.
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Affiliation(s)
- Parvin Mirmiran
- a Nutrition and Endocrine Research Center , Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Zahra Bahadoran
- a Nutrition and Endocrine Research Center , Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Mahdieh Golzarand
- a Nutrition and Endocrine Research Center , Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Golaleh Asghari
- a Nutrition and Endocrine Research Center , Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Fereidoun Azizi
- b Endocrine Research Center, Research Institute for Endocrine Sciences , Shahid Beheshti University of Medical Sciences , Tehran , Iran
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Maruyama D, Hirata N, Tokinaga Y, Kawaguchi R, Yamakage M. Nitrite Reduces Ischemia-Induced Ventricular Arrhythmias by Attenuating Connexin 43 Dephosphorylation in Rats. Anesth Analg 2016; 122:410-7. [DOI: 10.1213/ane.0000000000001063] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Hansen MN, Gerber L, Jensen FB. Nitric oxide availability in deeply hypoxic crucian carp: acute and chronic changes and utilization of ambient nitrite reservoirs. Am J Physiol Regul Integr Comp Physiol 2016; 310:R532-40. [PMID: 26764058 DOI: 10.1152/ajpregu.00515.2015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 01/06/2016] [Indexed: 11/22/2022]
Abstract
Recent research suggest that anoxia-tolerant fish transfer extracellular nitrite into the tissues, where it is used for nitric oxide (NO) generation, iron-nitrosylation, and S-nitrosation of proteins, as part of the cytoprotective response toward prolonged hypoxia and subsequent reoxygenation. We hypothesized that crucian carp take up ambient nitrite and use it as a source of cellular NO availability during hypoxia. Fish were exposed for 1 day to normoxia (Po2 > 140 mmHg) and deep hypoxia (1 < Po2 < 3 mmHg) at both low (< 0.2 μM) and moderately elevated (10 μM) ambient [nitrite] to decipher NO metabolites in plasma and several tissues. We also compared NO metabolite changes during acute (10 min) and chronic (1 day) exposures to three different O2 levels. Plasma [nitrite] decreased with decreasing [O2], while the cellular concentrations of nitrite and nitros(yl)ated compounds either increased or stayed constant, depending on O2 level and tissue type. Nitrite was notably increased in the heart during deep hypoxia, and the increase was amplified by elevated ambient [nitrite]. Raised nitrite also increased gill [nitrite] and decreased mRNA expression of an inducible nitric oxide synthase-2 gene variant. The data support that ambient nitrite is taken up across the gills to be distributed via the blood to the tissues, particularly the heart, where it assists in cytoprotection and other functions. Cardiac nitrite was not elevated in acutely exposed fish, revealing that the response requires time. NO metabolite levels were higher during acute than chronic exposures, possibly caused by increased swimming activity and stress in acutely exposed fish.
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Affiliation(s)
- Marie N Hansen
- Department of Biology, University of Southern Denmark, Odense M, Denmark
| | - Lucie Gerber
- Department of Biology, University of Southern Denmark, Odense M, Denmark
| | - Frank B Jensen
- Department of Biology, University of Southern Denmark, Odense M, Denmark
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Mohamed MSA. NO2- Mediates the Heart Protection of Remote Ischemic Preconditioning. Int J Organ Transplant Med 2016; 7:46-9. [PMID: 26889373 PMCID: PMC4756264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Cardioprotective effects of inorganic nitrate/nitrite in chronic anthracycline cardiotoxicity: Comparison with dexrazoxane. J Mol Cell Cardiol 2015; 91:92-103. [PMID: 26724189 DOI: 10.1016/j.yjmcc.2015.12.021] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 12/11/2015] [Accepted: 12/22/2015] [Indexed: 12/29/2022]
Abstract
Dexrazoxane (DEX) is a clinically available cardioprotectant that reduces the toxicity induced by anthracycline (ANT) anticancer drugs; however, DEX is seldom used and its action is poorly understood. Inorganic nitrate/nitrite has shown promising results in myocardial ischemia-reperfusion injury and recently in acute high-dose ANT cardiotoxicity. However, the utility of this approach for overcoming clinically more relevant chronic forms of cardiotoxicity remains elusive. Hence, in this study, the protective potential of inorganic nitrate and nitrite against chronic ANT cardiotoxicity was investigated, and the results were compared to those using DEX. Chronic cardiotoxicity was induced in rabbits with daunorubicin (DAU). Sodium nitrate (1g/L) was administered daily in drinking water, while sodium nitrite (0.15 or 5mg/kg) or DEX (60mg/kg) was administered parenterally before each DAU dose. Although oral nitrate induced a marked increase in plasma NOx, it showed no improvement in DAU-induced mortality, myocardial damage or heart failure. Instead, the higher nitrite dose reduced the incidence of end-stage cardiotoxicity, prevented related premature deaths and significantly ameliorated several molecular and cellular perturbations induced by DAU, particularly those concerning mitochondria. The latter result was also confirmed in vitro. Nevertheless, inorganic nitrite failed to prevent DAU-induced cardiac dysfunction and molecular remodeling in vivo and failed to overcome the cytotoxicity of DAU to cardiomyocytes in vitro. In contrast, DEX completely prevented all of the investigated molecular, cellular and functional perturbations that were induced by DAU. Our data suggest that the difference in cardioprotective efficacy between DEX and inorganic nitrite may be related to their different abilities to address a recently proposed upstream target for ANT in the heart - topoisomerase IIβ.
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Cao J, Xie H, Sun Y, Zhu J, Ying M, Qiao S, Shao Q, Wu H, Wang C. Sevoflurane post-conditioning reduces rat myocardial ischemia reperfusion injury through an increase in NOS and a decrease in phopshorylated NHE1 levels. Int J Mol Med 2015; 36:1529-37. [PMID: 26459736 PMCID: PMC4678156 DOI: 10.3892/ijmm.2015.2366] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 09/24/2015] [Indexed: 12/22/2022] Open
Abstract
The protective effects of sevoflurane post-conditioning against myocardial ischemia/reperfusion (I/R) injury (MIRI) have been previously reported. However, the mechanisms responsible for these protective effects remain elusive. In this study, in order to investigate the molecular mechanisms responsible for the protective effects of sevoflurane post-conditioning on isolated rat hearts subjected to MIRI, Sprague-Dawley rat hearts were randomly divided into the following 6 groups: i) the sham-operated control; ii) 2.5% sevoflurane; iii) ischemia/reperfusion (I/R); iv) 2.5% sevoflurane post-conditioning plus I/R; v) 2.5% sevoflurane post-conditioning + NG-nitro-L-arginine methyl ester (L-NAME) plus I/R; and vi) L-NAME plus I/R. The infarct size was measured using 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Additionally, the myocardial nitric oxide (NO), NO synthase (NOS) and nicotinamide adenine dinucleotide (NAD+) levels were determined. Autophagosomes and apoptosomes in the myocardium were detected by transmission electron microscopy. The levels of Bcl-2, cleaved caspase-3, Beclin-1, microtubule-associated protein light chain 3 (LC3)-I/II, Na+/H+ exchanger 1 (NHE1) and phosphorylated NHE1 protein were measured by western blot analysis. NHE1 mRNA levels were measured by reverse transcription-quantitative polymerase chain reaction. Compared with the I/R group, 15 min of exposure to 2.5% sevoflurane during early reperfusion significantly decreased the myocardial infarct size, the autophagic vacuole numbers, the NHE1 mRNA and protein expression of cleaved caspase-3, Beclin-1 and LC3-I/II. Post-conditioning with 2.5% sevoflurane also increased the NO and NOS levels and Bcl-2 protein expression (P<0.05 or P<0.01). Notably, the cardioprotective effects of sevoflurane were partly abolished by the NOS inhibitor, L-NAME. The findings of the present study suggest that sevoflurane post-conditioning protects the myocardium against I/R injury and reduces the myocardial infarct size. The underlying protective mechanisms are associated with the inhibition of mitochondrial permeability transition pore opening, and with the attenuation of cardiomyoctye apoptosis and excessive autophagy. These effects are mediated through an increase in NOS and a decrease in phopshorylated NHE1 levels.
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Affiliation(s)
- Jianfang Cao
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Hong Xie
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Ying Sun
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Jiang Zhu
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Ming Ying
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Shigang Qiao
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Qin Shao
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Haorong Wu
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Chen Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
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Rathod KS, Velmurugan S, Ahluwalia A. A 'green' diet-based approach to cardiovascular health? Is inorganic nitrate the answer? Mol Nutr Food Res 2015; 60:185-202. [PMID: 26256112 DOI: 10.1002/mnfr.201500313] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 06/16/2015] [Accepted: 07/10/2015] [Indexed: 12/22/2022]
Abstract
Ingestion of fruit and vegetables rich in inorganic nitrate (NO(3)(-)) has emerged as an effective method for acutely elevating vascular nitric oxide (NO) levels through formation of an NO(2)(-) intermediate. As such a number of beneficial effects of NO(3)(-) and NO(2)(-) ingestion have been demonstrated including reductions in blood pressure, measures of arterial stiffness and platelet activity. The pathway for NO generation from such dietary interventions involves the activity of facultative oral microflora that facilitate the reduction of inorganic NO(3)(-), ingested in the diet, to inorganic NO(2)(-). This NO(2)(-) then eventually enters the circulation where, through the activity of one or more of a range of distinct NO(2)(-) reductases, it is chemically reduced to NO. This pathway provides an alternative route for in vivo NO generation that could be utilized for therapeutic benefit in those cardiovascular disease states where reduced bioavailable NO is thought to contribute to pathogenesis. Indeed, the cardiovascular benefits of NO(2)(-) and NO(3)(-) are now starting to be translated in patients in several clinical trials. In this review, we discuss recent evidence supporting the potential utility of delivery of NO(3)(-) or NO(2)(-) for the treatment of cardiovascular diseases.
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Affiliation(s)
- Krishnaraj Sinhji Rathod
- William Harvey Research Institute, Barts NIHR Cardiovascular Biomedical Research Unit, Barts & The London Medical School, Queen Mary University of London, Charterhouse Square, London, UK
| | - Shanti Velmurugan
- William Harvey Research Institute, Barts NIHR Cardiovascular Biomedical Research Unit, Barts & The London Medical School, Queen Mary University of London, Charterhouse Square, London, UK
| | - Amrita Ahluwalia
- William Harvey Research Institute, Barts NIHR Cardiovascular Biomedical Research Unit, Barts & The London Medical School, Queen Mary University of London, Charterhouse Square, London, UK
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de Lima Portella R, Lynn Bickta J, Shiva S. Nitrite Confers Preconditioning and Cytoprotection After Ischemia/Reperfusion Injury Through the Modulation of Mitochondrial Function. Antioxid Redox Signal 2015; 23:307-27. [PMID: 26094636 DOI: 10.1089/ars.2015.6260] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
SIGNIFICANCE Nitrite is now recognized as an intrinsic signaling molecule that mediates a number of biological processes. One of the most reproducible effects of nitrite is its ability to mediate cytoprotection after ischemia/reperfusion (I/R). This robust phenomenon has been reproduced by a number of investigators in varying animal models focusing on different target organs. Furthermore, nitrite's cytoprotective versatility is highlighted by its ability to mediate delayed preconditioning and remote conditioning in addition to acute protection. RECENT ADVANCES In the last 10 years, significant progress has been made in elucidating the mechanisms underlying nitrite-mediated ischemic tolerance. CRITICAL ISSUES The mitochondrion, which is essential to both the progression of I/R injury and the protection afforded by preconditioning, has emerged as a major subcellular target for nitrite. This review will outline the role of the mitochondrion in I/R injury and preconditioning, review the accumulated preclinical studies demonstrating nitrite-mediated cytoprotection, and finally focus on the known interactions of nitrite with mitochondria and their role in the mechanism of nitrite-mediated ischemic tolerance. FUTURE DIRECTIONS These studies set the stage for current clinical trials testing the efficacy of nitrite to prevent warm and cold I/R injury.
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Affiliation(s)
- Rafael de Lima Portella
- 1 Vascular Medicine Institute, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Janelle Lynn Bickta
- 1 Vascular Medicine Institute, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.,2 Department of Bioengineering, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Sruti Shiva
- 1 Vascular Medicine Institute, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.,3 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.,4 Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
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Singamsetty S, Watanabe Y, Guo L, Corey C, Wang Y, Tejero J, McVerry BJ, Gladwin MT, Shiva S, O'Donnell CP. Inorganic nitrite improves components of the metabolic syndrome independent of weight change in a murine model of obesity and insulin resistance. J Physiol 2015; 593:3135-45. [PMID: 25952686 DOI: 10.1113/jp270386] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 04/27/2015] [Indexed: 01/08/2023] Open
Abstract
Nitrite acts as an endocrine source of bioactive nitric oxide, impacting vascular reactivity, angiogenesis and cytoprotection. Nitrite has recently been shown to have a metabolic role although its effects and mechanisms of action in the obese insulin-resistant state are unknown. We examined glucose tolerance and insulin secretion using the frequently sampled intravenous glucose tolerance test and insulin sensitivity using the hyperinsulinaemic euglycaemic clamp in obese male ob(lep) mice administered nitrite (100 mg kg(-1) day(-1) ) or saline (control) for 7 days and compared responses to the known insulin-sensitizing effects of rosiglitazone (6 mg kg(-1) day(-1) ). Under weight-matched conditions, nitrite lowered blood pressure relative to saline and rosiglitazone, whereas only rosiglitazone was effective at reducing hepatic glucose output and basal blood glucose. Both nitrite and rosiglitazone produced improvements, relative to saline, in glucose tolerance (12,524 ± 602, 12,811 ± 692 vs.14,428 ± 335 mg (dl min)(-1) , respectively; P < 0.05) and insulin sensitivity (8.6 ± 0.7, 7.9 ± 0.3 vs. 6.6 ± 0.5 mg kg(-1) min(-1) , respectively; P < 0.001), but there was no effect on insulin secretion. Nitrite exhibited an uncoupling of mitochondrial respiration and a decrease in ATP generation in muscle that was independent of mitochondrial biogenesis or activation of uncoupling proteins. There was no insulin-stimulated phosphorylation of Akt, but nitrite increased the phosphorylation of AMP-activated protein kinase. We conclude that nitrite improves two key components of the metabolic syndrome, blood pressure and insulin sensitivity, independent of weight and with effectiveness comparable to rosiglitazone.
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Affiliation(s)
- Srikanth Singamsetty
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA
| | - Yoshio Watanabe
- First Department of Internal Medicine, Showa University, School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan
| | - Lanping Guo
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA
| | - Catherine Corey
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA
| | - Yinna Wang
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA
| | - Jesus Tejero
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA
| | - Bryan J McVerry
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA
| | - Mark T Gladwin
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA
| | - Sruti Shiva
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA
| | - Christopher P O'Donnell
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA
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Kobayashi J, Ohtake K, Uchida H. NO-Rich Diet for Lifestyle-Related Diseases. Nutrients 2015; 7:4911-37. [PMID: 26091235 PMCID: PMC4488823 DOI: 10.3390/nu7064911] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 06/08/2015] [Accepted: 06/09/2015] [Indexed: 02/07/2023] Open
Abstract
Decreased nitric oxide (NO) availability due to obesity and endothelial dysfunction might be causally related to the development of lifestyle-related diseases such as insulin resistance, ischemic heart disease, and hypertension. In such situations, instead of impaired NO synthase (NOS)-dependent NO generation, the entero-salivary nitrate-nitrite-NO pathway might serve as a backup system for NO generation by transmitting NO activities in the various molecular forms including NO and protein S-nitrosothiols. Recently accumulated evidence has demonstrated that dietary intake of fruits and vegetables rich in nitrate/nitrite is an inexpensive and easily-practicable way to prevent insulin resistance and vascular endothelial dysfunction by increasing the NO availability; a NO-rich diet may also prevent other lifestyle-related diseases, including osteoporosis, chronic obstructive pulmonary disease (COPD), and cancer. This review provides an overview of our current knowledge of NO generation through the entero-salivary pathway and discusses its safety and preventive effects on lifestyle-related diseases.
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Affiliation(s)
- Jun Kobayashi
- Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Saitama 350-0295, Japan.
| | - Kazuo Ohtake
- Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Saitama 350-0295, Japan.
| | - Hiroyuki Uchida
- Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Saitama 350-0295, Japan.
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Kovács M, Kiss A, Gönczi M, Miskolczi G, Seprényi G, Kaszaki J, Kohr MJ, Murphy E, Végh Á. Effect of sodium nitrite on ischaemia and reperfusion-induced arrhythmias in anaesthetized dogs: is protein S-nitrosylation involved? PLoS One 2015; 10:e0122243. [PMID: 25909651 PMCID: PMC4409072 DOI: 10.1371/journal.pone.0122243] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 02/18/2015] [Indexed: 11/21/2022] Open
Abstract
Background and Purpose To provide evidence for the protective role of inorganic nitrite against acute ischaemia and reperfusion-induced ventricular arrhythmias in a large animal model. Experimental Approach Dogs, anaesthetized with chloralose and urethane, were administered intravenously with sodium nitrite (0.2 µmolkg-1min-1) in two protocols. In protocol 1 nitrite was infused 10 min prior to and during a 25 min occlusion of the left anterior descending (LAD) coronary artery (NaNO2-PO; n = 14), whereas in protocol 2 the infusion was started 10 min prior to reperfusion of the occluded vessel (NaNO2-PR; n = 12). Control dogs (n = 15) were infused with saline and subjected to the same period of ischaemia and reperfusion. Severities of ischaemia and ventricular arrhythmias, as well as changes in plasma nitrate/nitrite (NOx) levels in the coronary sinus blood, were assessed throughout the experiment. Myocardial superoxide and nitrotyrosine (NT) levels were determined during reperfusion. Changes in protein S-nitrosylation (SNO) and S-glutathionylation were also examined. Key Results Compared with controls, sodium nitrite administered either pre-occlusion or pre-reperfusion markedly suppressed the number and severity of ventricular arrhythmias during occlusion and increased survival (0% vs. 50 and 92%) upon reperfusion. There were also significant decreases in superoxide and NT levels in the nitrite treated dogs. Compared with controls, increased SNO was found only in NaNO2-PR dogs, whereas S-glutathionylation occurred primarily in NaNO2-PO dogs. Conclusions Intravenous infusion of nitrite profoundly reduced the severity of ventricular arrhythmias resulting from acute ischaemia and reperfusion in anaesthetized dogs. This effect, among several others, may result from an NO-mediated reduction in oxidative stress, perhaps through protein SNO and/or S-glutathionylation.
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Affiliation(s)
- Mária Kovács
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Attila Kiss
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Márton Gönczi
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Gottfried Miskolczi
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - György Seprényi
- Department of Medical Biology, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - József Kaszaki
- Institute of Surgical Research, Albert Szent-Györgyi Medical Center, University of Szeged, Szeged, Hungary
| | - Mark J Kohr
- Systems Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Elizabeth Murphy
- Systems Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Ágnes Végh
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary
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Hsieh A, Feric NT, Radisic M. Combined hypoxia and sodium nitrite pretreatment for cardiomyocyte protection in vitro. Biotechnol Prog 2015; 31:482-92. [PMID: 25582867 DOI: 10.1002/btpr.2039] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 11/24/2014] [Indexed: 11/08/2022]
Abstract
Methods that increase cardiomyocyte survival upon exposure to ischemia, hypoxia and reoxygenation injuries are required to improve the efficacy of cardiac cell therapy and enhance the viability and function of engineered tissues. We investigated the effect of combined hypoxia/NaNO2 pretreatment on rat neonatal cardiomyocyte (CM), cardiac fibroblast, and human embryonic stem cell-derived CM (hESC-CM) survival upon exposure to hypoxia/reoxygenation (H/R) injury in vitro. Cells were pretreated with and without hypoxia and/or various concentrations of NaNO2 for 20 min, then incubated for 2 h under hypoxic conditions, followed by 2 h in normoxia. The control cells were maintained under normoxia for 4 h. Pretreatment with either hypoxia or NaNO2 significantly increased CM viability but had no effect on cardiac fibroblast viability. Combined hypoxia/NaNO2 pretreatment significantly increased CM viability but significantly decreased cardiac fibroblast viability. In rat neonatal CMs, cell death, as determined by lactate dehydrogenase (LDH) activity, was significantly reduced with hypoxia/NaNO2 pretreatment; and in hESC-CMs, hypoxia/NaNO2 pretreatment increased the BCL-2/BAX gene expression ratio, suggesting that hypoxia/NaNO2 pretreatment promotes cell viability by downregulating apoptosis. Additionally, we found a correlation between the prosurvival effect of hypoxia/NaNO2 pretreatment and the myoglobin content of the cells by comparing neonatal rat ventricular and atrial CMs, which express high and low myoglobin respectively. Functionally, hypoxia/NaNO2 pretreatment significantly improved the excitation threshold upon H/R injury to the level observed for uninjured cells, whereas pretreatment did not affect the maximum capture rate. Hence, hypoxia/NaNO2 pretreatment may serve as a strategy to increase CM survival in cardiac regenerative therapy applications and tissue engineering.
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Affiliation(s)
- Anne Hsieh
- Dept. of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
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Björnsson B, Bojmar L, Olsson H, Sundqvist T, Sandström P. Nitrite, a novel method to decrease ischemia/reperfusion injury in the rat liver. World J Gastroenterol 2015; 21:1775-1783. [PMID: 25684942 PMCID: PMC4323453 DOI: 10.3748/wjg.v21.i6.1775] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 08/24/2014] [Accepted: 10/15/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether nitrite administered prior to ischemia/reperfusion (I/R) reduces liver injury.
METHODS: Thirty-six male Sprague-Dawley rats were randomized to 3 groups, including sham operated (n = 8), 45-min segmental ischemia of the left liver lobe (IR, n = 14) and ischemia/reperfusion (I/R) preceded by the administration of 480 nmol of nitrite (n = 14). Serum transaminases were measured after 4 h of reperfusion. Liver microdialysate (MD) was sampled in 30-min intervals and analyzed for glucose, lactate, pyruvate and glycerol as well as the total nitrite and nitrate (NOx). The NOx was measured in serum.
RESULTS: Aspartate aminotransferase (AST) at the end of reperfusion was higher in the IR group than in the nitrite group (40 ± 6.8 μkat/L vs 22 ± 2.6 μkat/L, P = 0.022). Similarly, alanine aminotransferase (ALT) was also higher in the I/R group than in the nitrite group (34 ± 6 μkat vs 14 ± 1.5 μkat, P = 0.0045). The NOx in MD was significantly higher in the nitrite group than in the I/R group (10.1 ± 2.9 μmol/L vs 3.2 ± 0.9 μmol/L, P = 0.031) after the administration of nitrite. During ischemia, the levels decreased in both groups and then increased again during reperfusion. At the end of reperfusion, there was a tendency towards a higher NOx in the I/R group than in the nitrite group (11.6 ± 0.7 μmol/L vs 9.2 ± 1.1 μmol/L, P = 0.067). Lactate in MD was significantly higher in the IR group than in the nitrite group (3.37 ± 0.18 mmol/L vs 2.8 ± 0.12 mmol/L, P = 0.01) during ischemia and the first 30 min of reperfusion. During the same period, glycerol was also higher in the IRI group than in the nitrite group (464 ± 38 μmol/L vs 367 ± 31 μmol/L, P = 0.049). With respect to histology, there were more signs of tissue damage in the I/R group than in the nitrite group, and 29% of the animals in the I/R group exhibited necrosis compared with none in the nitrite group. Inducible nitric oxide synthase transcription increased between early ischemia (t = 15) and the end of reperfusion in both groups.
CONCLUSION: Nitrite administered before liver ischemia in the rat liver reduces anaerobic metabolism and cell necrosis, which could be important in the clinical setting.
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Nitrite reduction by molybdoenzymes: a new class of nitric oxide-forming nitrite reductases. J Biol Inorg Chem 2015; 20:403-33. [DOI: 10.1007/s00775-014-1234-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 12/14/2014] [Indexed: 02/07/2023]
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Fukuda T, Kakinohana M, Takayama C, Matsushita M, Sugahara K. Dietary supplementation with sodium nitrite can exert neuroprotective effects on global cerebral ischemia/reperfusion in mice. J Anesth 2015; 29:609-17. [PMID: 25566835 DOI: 10.1007/s00540-014-1968-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 12/20/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Nitrite-derived NO protects against middle cerebral artery occlusion in mice. We developed a new mouse model of global cerebral ischemia and reperfusion (GCI/R) involving reversible occlusion of the major vessels from the aortic arch supplying the brain, and investigated neuroprotection with dietary sodium nitrite supplementation against GCI/R injury. METHODS Mice received drinking water with (nitrite group) or without (control group) sodium nitrite (2 mM) for 5 days and underwent 3-min GCI/R by reversible occlusion of major vessels from the aortic arch (i.e., brachiocephalic, left common carotid, and left subclavian artery). Survival rates and neurological function scores were evaluated for up to 5 days after GCI/R. Histopathological studies were performed to detect neurological degeneration and caspase-3 activation in serial hippocampal sections. RESULTS In the control group, 17/30 mice (57 %) survived 5 days after 3-min GCI/R, whereas in the nitrite group 25/30 mice (83 %) survived (p < 0.05). The neurological score at 5 days after GCI in control group was significantly higher than in the nitrite group. Cerebral blood flow (CBF) during GCI was significantly higher in the nitrite group than in the control group, while MABP did not differ significantly between groups. Degenerative changes and caspase-3 activation in hippocampal sections after GCI were observed in the control group but not in the nitrite group. Pretreatment with the NO scavenger c-PTIO abolished the neuroprotective effects of sodium nitrite. CONCLUSIONS Sodium nitrite supplementation attenuated mortality and neurological impairment after 3-min GCI in mice; an effect likely mediated via vascular mechanisms involving NO.
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Affiliation(s)
- Takasuke Fukuda
- Department of Anesthesiology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan,
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Jones DA, Pellaton C, Velmurugan S, Rathod KS, Andiapen M, Antoniou S, van Eijl S, Webb AJ, Westwood MA, Parmar MK, Mathur A, Ahluwalia A. Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. Circ Res 2014; 116:437-47. [PMID: 25512434 DOI: 10.1161/circresaha.116.305082] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
RATIONALE Preclinical evidence demonstrates that inorganic nitrite, after its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury. OBJECTIVE We investigated whether intracoronary injection of nitrite during primary percutaneous coronary intervention might improve infarct size in ST-elevated myocardial infarction. METHODS AND RESULTS Patients undergoing primary percutaneous coronary intervention (n=80) were randomized to receive intracoronary (10 mL) sodium nitrite (1.8 μmol) or NaCl (placebo) before balloon inflation. The primary end point was infarct size assessed by measuring creatine kinase release. Secondary outcomes included infarct size assessed by troponin T release and by cardiac MRI on day 2. Baseline characteristics were similar between the groups. No evidence of differences in creatine kinase release (P=0.92), troponin T (P=0.85), or cardiac MRI-assessed infarct size (P=0.254) were evident. In contrast, there was an improvement [corrected] in myocardial salvage index (P=0.05) and reduction in [corrected] major adverse cardiac event at 1 year (2.6% versus 15.8%; P=0.04) in the nitrite group. In a 66-patient subgroup with thrombolysis in myocardial infarction ≤1 flow, there was reduced serum creatine kinase (P=0.030) and a 19% reduction in cardiac MRI-determined infarct size (P=0.034) with nitrite. No adverse effects of nitrite were detected. CONCLUSIONS In this phase II study, intracoronary nitrite infusion did not alter infarct size, although a trend to improved myocardial salvage index and a significant reduction in major adverse cardiac event was evident. In a subgroup of patients with thrombolysis in myocardial infarction flow ≤1, nitrite reduced infarct size and major adverse cardiac event and improved myocardial salvage index, indicating that a phase III clinical trial assessing intracoronary nitrite administration as an adjunct to percutaneous coronary intervention in ST-elevated myocardial infarction patients is warranted. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCT01584453.
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Affiliation(s)
- Daniel A Jones
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Cyril Pellaton
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Shanti Velmurugan
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Krishnaraj Sinha Rathod
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Mervyn Andiapen
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Sotiris Antoniou
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Sven van Eijl
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Andrew J Webb
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Mark A Westwood
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Mahesh K Parmar
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Anthony Mathur
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK
| | - Amrita Ahluwalia
- From the Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London Medical School (D.A.J., S.V., K.S.R., S.A., S.v.E., A.J.W., A.M., A.A.); and Department of Cardiology, London Chest Hospital, Barts Health NHS Trust (D.A.J., C.P., S.V., M.A., M.A.W., A.M.), and MRC Clinical Trials Unit at UCL (M.K.P.), University College London, Aviation House, Kingsway, London, UK.
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Harisa GI, Mariee AD, Abo-Salem OM, Attiaa SM. Erythrocyte nitric oxide synthase as a surrogate marker for mercury-induced vascular damage: the modulatory effects of naringin. ENVIRONMENTAL TOXICOLOGY 2014; 29:1314-1322. [PMID: 23650045 DOI: 10.1002/tox.21862] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 03/02/2013] [Accepted: 03/05/2013] [Indexed: 06/02/2023]
Abstract
In this study, endothelial nitric oxide synthase activity and nitric oxide (NO) production by human erythrocytes in the presence and absence of mercuric chloride (HgCl2 ), L-arginine (L-ARG), N ω- nitro-L-arginine methyl ester (L-NAME), and naringin (NAR) were investigated. In addition, the levels of reduced glutathione (GSH) and related enzymes were estimated in erythrocytes hemolysate. The protein carbonyl content (PCC) and thiobarbituric acid-reactive substances (TBARS) levels were also determined. The results of this study revealed that the treatment of erythrocytes with either HgCl2 or L-NAME induced a significant decrease in NOS activity and nitrite levels compared with control cells. Furthermore, mercury exposure significantly increased the levels of PCC and TBARS but reduced the GSH level. The activities of glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, and glutathione-S-transferase (GST) were inhibited. The exposure of erythrocytes to HgCl2 in combination with L-ARG, NAR, or both ameliorated the investigated parameters compared with erythrocytes incubated with HgCl2 alone. These results indicate that mercury exposure decreased both erythrocyte NOS activity and nitrite production, and that these parameters might be indicative of mercury exposure. The data also suggest that concomitant treatment with NAR can restore NO bioavailability through either its metal-chelating properties or its antioxidant activity.
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Affiliation(s)
- Gamaleldin I Harisa
- Department of Pharmaceutics, Kayyali Chair for Pharmaceutical Industry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Biochemistry, College of Pharmacy, Al-Azhar University (Boys), Cairo, Egypt
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