Cover photo credit: Girouard H., and Tabatabaei S.N Nitric Oxide and Cerebrovascular Regulation Vitamins and Hormones (2014) 96, pp 347–386 Academic Press is an imprint of Elsevier 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 32 Jamestown Road, London NW1 7BY, UK The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First edition 2014 Copyright © 2014 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual 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contained in the material herein ISBN: 978-0-12-800254-4 ISSN: 0083-6729 For information on all Academic Press publications visit our website at store.elsevier.com Printed and bound in USA Former Editors ROBERT S HARRIS KENNETH V THIMANN Newton, Massachusetts University of California Santa Cruz, California JOHN A LORRAINE University of Edinburgh Edinburgh, Scotland PAUL L MUNSON University of North Carolina Chapel Hill, North Carolina JOHN GLOVER University of Liverpool Liverpool, England GERALD D AURBACH Metabolic Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland IRA G WOOL University of Chicago Chicago, Illinois EGON DICZFALUSY Karolinska Sjukhuset Stockholm, Sweden ROBERT OLSEN School of Medicine State University of New York at Stony Brook Stony Brook, New York DONALD B MCCORMICK Department of Biochemistry Emory University School of Medicine, Atlanta, Georgia CONTRIBUTORS Ashok Aiyar Stanley S Scott Cancer Center, Louisiana State University, Health Sciences Center, New Orleans, Louisiana, USA Alexis Bavencoffe Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Karin C Calaza Programa de Neurocieˆncias, and Departamento de Neurobiologia, Instituto de Biologia, Universidade Federal Fluminense, Nitero´i, RJ, Brazil Paula Campello-Costa Programa de Neurocieˆncias, and Departamento de Neurobiologia, Instituto de Biologia, Universidade Federal Fluminense, Nitero´i, RJ, Brazil Shao-Rui Chen Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Angela Cheung Division of Developmental Neurobiology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom Marcelo Cossenza Programa de Neurocieˆncias, Instituto de Biologia, Nitero´i, RJ, and Departamento de Fisiologia e Farmacologia, Instituto Biome´dico, Universidade Federal Fluminense, Rio de Janeiro, Brazil Ivan C.L Domith Programa de Neurocieˆncias, Instituto de Biologia, Universidade Federal Fluminense, Nitero´i, RJ, Brazil Thaı´sa G Encarnac¸a˜o Programa de Neurocieˆncias, Instituto de Biologia, Universidade Federal Fluminense, Nitero´i, RJ, Brazil David A Geller Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA He´le`ne Girouard Department of Pharmacology, Faculty of Medicine, Universite´ de Montre´al, and Research Center of the Institut Universitaire de Ge´riatrie de Montre´al, Montreal, Quebec, Canada xiii xiv Contributors Luis F.H Gladulich Programa de Neurocieˆncias, Instituto de Biologia, Universidade Federal Fluminense, Nitero´i, RJ, Brazil William P Gray Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom Zhong Guo Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Bradford G Hill Diabetes and Obesity Center, Institute of Molecular Cardiology; Department of Physiology and Biophysics, and Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, USA Michael A Hough School of Biological Sciences, University of Essex, Colchester, United Kingdom Yao Hu Institute for Stem Cells and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing, China H.S Jeffrey Man Institute of Medical Science; Li Ka Shing Knowledge Institute, St Michael’s Hospital, and Divisions of Respirology and Critical Care Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada Jisha Joshua Department of Medicine, University of California, San Diego, California, USA Hema Kalyanaraman Department of Medicine, University of California, San Diego, California, USA Sangwon F Kim Department of Psychiatry and Pharmacology, Center for Neurobiology and Behavior, The Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania, USA Peter Kruzliak Department of Cardiovascular Diseases, International Clinical Research Center, St Anne’s University Hospital, Brno, Czech Republic Nisha Marathe Department of Medicine, University of California, San Diego, California, USA Philip A Marsden Institute of Medical Science; Li Ka Shing Knowledge Institute, St Michael’s Hospital, and Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada Junko Maruyama Department of Anesthesiology and Critical Care Medicine, Mie University School of Medicine, and Department of Clinical Engineering, Suzuka University of Medical Science, Mie, Japan Contributors xv Kazuo Maruyama Department of Anesthesiology and Critical Care Medicine, Mie University School of Medicine, and Department of Clinical Engineering, Suzuka University of Medical Science, Mie, Japan Henrique R Mendonc¸a Programa de Neurocieˆncias, Instituto de Biologia, Universidade Federal Fluminense, Nitero´i, RJ, Brazil Roberto Paes-de-Carvalho Programa de Neurocieˆncias, and Departamento de Neurobiologia, Instituto de Biologia, Universidade Federal Fluminense, Nitero´i, RJ, Brazil Hui-Lin Pan Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Renate B Pilz Department of Medicine, University of California, San Diego, California, USA Camila C Portugal Programa de Neurocieˆncias, Instituto de Biologia, Universidade Federal Fluminense, Nitero´i, RJ, Brazil Brian E Sansbury Diabetes and Obesity Center, Institute of Molecular Cardiology, and Department of Physiology and Biophysics, Louisville, Kentucky, USA Gary Silkstone School of Biological Sciences, University of Essex, Colchester, United Kingdom Renato Socodato Programa de Neurocieˆncias, Instituto de Biologia, Universidade Federal Fluminense, Nitero´i, RJ, Brazil Seyed Nasrollah Tabatabaei Department of Computer and Software Engineering and Institute of Biomedical cole Polytechnique de Montre´al Engineering, E David Tate Stanley S Scott Cancer Center, Louisiana State University, Health Sciences Center, New Orleans, Louisiana, USA Douglas D Thomas Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA Albert K.Y Tsui Li Ka Shing Knowledge Institute, and Department of Anesthesia, St Michael’s Hospital, Toronto, Ontario, Canada Laura B Valdez Institute of Biochemistry and Molecular Medicine (IBIMOL), Physical Chemistry Division, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina xvi Contributors Divya Vasudevan Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA Cecilia Vecoli Institute of Clinical Physiology-CNR, Pisa, Italy Michael T Wilson School of Biological Sciences, University of Essex, Colchester, United Kingdom Jonathan Worrall School of Biological Sciences, University of Essex, Colchester, United Kingdom Tamara Zaobornyj Institute of Biochemistry and Molecular Medicine (IBIMOL), Physical Chemistry Division, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina Arnold H Zea Stanley S Scott Cancer Center, Louisiana State University, Health Sciences Center, New Orleans, Louisiana, USA Dong-Ya Zhu Institute for Stem Cells and Neural Regeneration, and Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China PREFACE Nitric oxide (nitrogen monoxide, NO), a gaseous molecule, is derived from the amino acid, L-arginine, in the human body Its discovery was a great surprise because other hormones and regulators in the body are made up of proteins, lipid-derived compounds, and other molecules, none of which are gaseous NO affects a number of enzyme systems and binds to heme, a cofactor in some important enzymes In many ways, NO acts as a hormone and regulates many processes Its activities are generally beneficial For example, it is a powerful generator of vasodilation by suppressing vascular smooth muscle contraction Its action is rapid as it remains in the blood for only seconds In other activities, NO inhibits platelet aggregation and the adhesion of leukocytes to endothelia Poorly functioning pathways involving NO are hallmarks in patients with various diseases, such as diabetes, atherosclerosis, and hypertension Consequently, nitric oxide becomes a substance of interest in therapeutic applications Many of the properties and actions of this new regulator, nitric oxide, are reviewed in this volume Reviews in this book have been ordered by first introducing the basic aspects of nitric oxide followed by chapters that involve clinical concepts Accordingly, the first chapter is on the “Regulation of nociceptive transduction and transmission by nitric oxide” by A Bavencoffe, S.-R Chen, and H.-L Pan The next offering is by Z Guo and D.A Geller entitled “microRNA and human inducible nitric oxide synthase.” “Heart mitochondrial nitric oxide synthase: a strategic enzyme in the regulation of cellular bioenergetics” is authored by T Zaobornyj and L.B Valdez W.P Gray and A Cheung review “Nitric oxide regulation of adult neurogenesis.” “Nitric oxide in the nervous system: biochemical, developmental, and neurobiological aspects” is the work of M Cossenza, R Socodato, C.C Portugal, I.C.L Domith, L.F.H Gladulich, T.G Encarnac¸a˜o, K.C Kalaza, H.R Mendonc¸a, P Campello-Costa, and R Paes-de-Carvalho Y Hu and D.-Y Zhu report on “Hippocampus and nitric oxide.” “Nitric oxide and hypoxia signaling” is a review by H.S.J Man, A.K.Y Tsui, and P.A Marsden M.A Hough, G Silkstone, J Worrall, and M.T Wilson discuss “NO binding to the proapoptotic cytochrome c–cardiolipin complex.” S.F Kim writes on “The nitric oxide-mediated regulation of prostaglandin signaling in medicine.” xvii xviii Preface “Nitric oxide as a mediator of estrogen effects in osteocytes” is the topic of J Joshua, H Kalyanaraman, N Marathe, and R.B Pilz In aspects related to disease conditions, contributions begin with “Insights into the diverse effects of nitric oxide on tumor biology” by D Vasudevan and D.D Thomas A.H Zea, A Aiyar, and D Tate review “Dual effect of interferon (IFNγ)-induced nitric oxide on tumorigenesis and intracellular bacteria.” Next, B.E Sansbury and B.G Hill cover the “Anti-obesogenic role of endothelial nitric oxide synthase.” H Girouard and S.N Tabatabaei report on “Nitric oxide and cerebrovascular regulation.” Then, C Vecoli reports on “Endothelial nitric oxide synthase gene polymorphisms in cardiovascular disease.” The “Role of nitric oxide in pathophysiology and treatment of pulmonary hypertension” by P Kruzliak, J Maruyama, and K Maruyama is the final chapter The cover illustration is Fig 14.2 of Chapter 14 Helene Kabes and Mary Ann Zimmerman of Elsevier, Oxford, UK were instrumental in the processing of these chapters GERALD LITWACK North Hollywood, California May 8, 2014 CHAPTER ONE Regulation of Nociceptive Transduction and Transmission by Nitric Oxide Alexis Bavencoffe, Shao-Rui Chen, Hui-Lin Pan1 Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Corresponding author: e-mail address: huilinpan@mdanderson.org Contents Introduction Role of NO in Nociceptive Transduction at the Periphery Diverse Effects of NO on Ion Channels Expressed on Primary Sensory Neurons 3.1 Acid-sensing ion channels 3.2 Transient receptor potential channels 3.3 KATP channels Role of NO in Regulating Nociceptive Transmission at the Spinal Cord Level NO Reduces Excitatory, But Potentiates Inhibitory, Synaptic Transmission in Spinal Cords 5.1 Glutamatergic input from primary afferent nerves 5.2 Voltage-activated calcium channels in sensory neurons 5.3 Synaptic NMDA receptors 5.4 Synaptic release of glycine Conclusions and Future Directions Acknowledgments References 5 7 10 11 11 11 12 14 14 Abstract The potential involvement of nitric oxide (NO), a diffusible gaseous signaling messenger, in nociceptive transduction and transmission has been extensively investigated However, there is no consistent and convincing evidence supporting the pronociceptive action of NO at the physiological concentration, and the discrepancies are possibly due to the nonspecificity of nitric oxide synthase inhibitors and different concentrations of NO donors used in various studies At the spinal cord level, NO predominantly reduces synaptic transmission by inhibiting the activity of NMDA receptors and glutamate release from primary afferent terminals through S-nitrosylation of voltageactivated calcium channels NO also promotes synaptic glycine release from inhibitory Vitamins and Hormones, Volume 96 ISSN 0083-6729 http://dx.doi.org/10.1016/B978-0-12-800254-4.00001-5 # 2014 Elsevier Inc All rights reserved Alexis Bavencoffe et al interneurons through the cyclic guanosine monophosphate/protein kinase G signaling pathway Thus, NO probably functions as a negative feedback regulator to reduce nociceptive transmission in the spinal dorsal horn during painful conditions INTRODUCTION Pain receptors, also called nociceptors, are a group of sensory neurons with specialized nerve endings widely distributed in the skin, deep tissues (including the muscles and joints), and most of visceral organs They respond to tissue injury or potentially damaging stimuli by sending nerve signals to the spinal cord and brain to begin the process of pain sensation Nociceptors are equipped with specific molecular sensors, which detect extreme heat or cold and certain harmful chemicals Mechanical nociceptors can also respond to tissue-damaging stimuli, such as pinching the skin or overstretching the muscles Activation of nociceptors generates action potentials, which are propagated along the afferent nerve axons, especially unmyelinated C-fibers and thinly myelinated Aδ-fibers At the spinal cord level, the nociceptive nerve terminals release excitatory neurotransmitters to activate their respective postsynaptic receptors on second-order neurons In the spinal dorsal horn, both excitatory and inhibitory interneurons can augment or attenuate nociceptive transmission (Cervero & Iggo, 1980; Zhou, Zhang, Chen, & Pan, 2007, 2008) The nociceptive signal, encoding the quality, location, and intensity of the noxious stimuli, is then conveyed via the ascending pathway to reach various brain regions to elicit pain sensation Physiological pain responses normally protect us from tissue damage by quickly alerting us to impending injury Unlike acute physiological pain, chronic pathological pain, including neuropathic and inflammatory pain, is often associated with increased activity and responses of spinal dorsal horn neurons, termed central sensitization (Woolf & Thompson, 1991; Xu, Dalsgaard, & Wiesenfeld-Hallin, 1992) This phenomenon is the cellular basis for hyperalgesia (increased pain response to a noxious stimulus) and allodynia (painful sensation in response to a nonnoxious stimulus) Nitric oxide (NO) is a membrane-permeable gaseous second messenger involved in signal transduction The physiological function of NO has been shown in a large variety of cell types and tissues, including the immune system, blood vessels, endothelial cells, and neurons NO is produced from L-arginine by three major isoforms of nitric oxide synthase (NOS): neuronal 422 Peter Kruzliak et al Kinsella, J P., Neish, S R., Shaffer, E., & Abman, S H (1992) Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn Lancet, 340(8823), 819–820 Kobayashi, T., Gabazza, E C., Shimizu, S., Yasui, H., Yuda, H., Hataji, O., et al (2001) Long-term inhalation of high-dose nitric oxide increases 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figures and “t ” indicate tables A Acid-sensing ion channels (ASIC), Acute lung injury, 418 AD See Alzheimer’s disease (AD) Adipose tissue See also Antiobesogenic role, eNOS eNOS, 327, 332, 333f PPARα expression, 332–334 sildenafil, mitochondrial biogenesis, 330–331 Adult neurogenesis dual effect, NO, 67–70 embryonic development, 60 hippocampus, 61–62 humans and rodents, 61 learning and memory, synaptic plasticity, 136 neural precursor cells, 60–61 NO–cGMP–PKG pathway, 70–72 NOS expression, in neurogenic regions, 62–63 and NOS knockout animals, 64–65 NPYand NO, 65–67 pharmacological studies, NO, 63–64 SGZ (see Subgranular zone (SGZ)) SVZ (see Subventricular zone (SVZ)) Adult respiratory distress syndrome, 418 AKT modulation by NO, 89–91 AKT phosphorylation concentration-dependent %NO responses, 273–274 PI3K inhibitor LY294002, 258–259 Ser473 and Thr308, 89–91, 90f Alzheimer’s disease (AD) amygdalar and hippocampal atrophies, 147–148 amyloid-β (Aβ), 147–148 Ca2+ homeostasis dysfunction, 148 COX-2 expression, 148 eNOS-derived NO, 148–149 NO/cGMP signaling, 148 prevalence, 147 Anemia blood transfusion and ESAs, 163–164 cardiovascular adaptation, 175–176 vs hypoxia blood oxygen content, 172–174, 173f GSNOR-deficient mice, 174 nNOS (– / –) mice, 171–172 treatment, 171 metabolic adaptation, 176 respiratory adaptation, 176 tissue oxygen extraction, 177 Angiogenesis description, 280 %NO donors, VEGF upregulation, 281 prostaglandin E2 (PGE2), 280 tumor neovascularization, 280–281 VEGF and prostaglandins, 280 Antiobesogenic role, eNOS adiposity and insulin sensitivity, NO, 324–325 eNOS-derived NO, 334 insulin resistance, 324 NO bioavailability, in obese and diabetic states, 326–330 obesity and insulin resistance, regulation, 330–334 vascular and metabolic function, 325–326 Apoptosis BAD phosphorylation, 257–258 17β-estradiol, 250 estradiol-and cGMP-mediated protection, 256 etoposide-induced, 257 NO/cGMP signaling, 254–255 osteoclast, 249 osteocyte, 249–250, 257–258 Apoptosis signal-regulating kinase (ASK1), 94–95 Apoptosome, 196–197 ASIC See Acid-sensing ion channels (ASIC) ASK1 See Apoptosis signal-regulating kinase (ASK1) 425 426 Atrial fibrillation (AF), 397–398 Autoregulation arterial pressure, 359–360 CBF autoregulatory curve, 358 definition, 348–349 dynamic cerebral autoregulation, 360 eNOS, 360 in lower limit, 358 NMDA receptor blocker, 359 nNOS-knockout mice, 359 noradrenaline administration, 358–359 NOS inhibitor, topical application, 358 potassium administration, channel activator, 358 B Biotin switch assay, 233 Bronchopulmonary dysplasia, 417–418 C cAMP-responsive element-binding protein (CREB) bdnf gene, 85 ERK1/2 phosphorylation, 92, 109–110 NO production and signaling, 92, 93f nuclear transcription factor, 138 phosphorylation and protein synthesis, 108–109 Cancer eNOS polymorphisms, 399 etiology chronic inflammation, 275 DNA damage, 275–276 and p53, 276–277 peroxynitrite, 275–276 histone demethylase, 274–275 JS-K, 287–288 low %NO fluxes, 274 NOS2/NO system (see NOS2/NO system) progression angiogenesis, 280–281 EMT, 281–284 epigenetics, 284–286 hypoxic tumors, 277–278 NOS, 278–280 treatment GT-094, 287–288 Index JS-K, 287–288 NO–NSAIDs, 287–288 NOS inhibitors and %NO donors, 287 Carboxyl-terminal PDZ ligand of NOS (CAPON), 86f, 87–88 Cardiovascular adaptation, anemia, 175–176 Cardiovascular disease (CVD) atrial fibrillation (AF), 397–398 CAD and myocardial infarction, 392–394 dilated cardiomyopathy (DCM), 397–398 hypertension, 394–396 ischemic stroke (IS), 396–397 pre-eclampsia (PE), 396 Caveolin-1 and eNOS uncoupling, 411 Cerebral blood flow (CBF) autoregulation, 358–360 NO role, 348–349 NVC, 360–370 resting, 350–357 Cerebrovascular regulation autoregulation (see Autoregulation) NO source, 349–350 NVC (see Neurovascular coupling (NVC)) resting CBF (see Resting CBF) cGMP-dependent protein kinases (PKGs) osteocyte survival, 254–259 PKG I and II, 253 Chelatable iron pool (CIP), 270, 284–285 Chronic hypoxia adaptation, 47 NO release, 47–48 O2 availability, 47–48 rat heart mtNOS activity and expression, 47 Chronic obstructive pulmonary disease (COPD), 418–419 Citrulline L-Arg de novo synthesis, 303–304, 304f, 306–307 in blood, 305–306 NOS catabolize L-arginine, 300–301 NOS colocalization, 306–307 supplementation, 306–307 COPD See Chronic obstructive pulmonary disease (COPD) Coronary artery disease (CAD) and myocardial infarction, 392–394 427 Index COXs See Cyclooxygenases (COXs) CREB See cAMP-responsive elementbinding protein (CREB) CREB modulation by NO, 92 Cyclooxygenases (COXs) COX1 and-2 and arachidonic acid, 218–219 domains, 219 enzyme reaction mechanism, 219–221, 220f expression patterns and localization, 221–222 heterodimer formation, 221–222 human, 219 in vitro and in vivo, 218 S-nitrosylation, 233–234 Cytochrome c-cardiolipin (cyt c–CL) complex and NO binding apoptosis regulation, 194 apoptosome, 196–197 electron carrier, 195–196 enzyme, conformational transition, 194 heme-iron Met ligand, 196–197 heme proteins, 194–195 human cyt c, functional role schematic, 195–196, 196f ligand binding to Alcaligenes xylosoxidans cytochrome c0 (Ax cytc0 ), 199f, 200–201 CO binding, second-order rate constant, 197–198 ferro-cyt c/CL has spectroscopic properties, 198–200 NO concentration, 198 penta-coordinate heme proteins, 197–198 pentacoordinate NO complex, 199f, 200–201 proximal NO binding to Ax cyt c0 , 198–200, 201–203, 202f Soret band, 198–200 spectral intermediates, ferrous cyt c/CL complex and NO reaction, 198–200, 199f time-resolved optical spectra, 200–201 mitochondrial cyt c, 195–196 mitochondrial outer membrane permeabilization, 196–197 phosphatidylserine (PS), 197 phospholipid and cardiolipin (CL), molecular structure, 195, 195f proximal NO complex, nature and formation axial Met-heme ligand, 203 cyt c and Ax cyt c, 203 distal-to-proximal NO conversion, 204 fluorescence (FRET) experiments, 203–204 trans effects, 203–204 D DA release See Dopamine (DA) release Diabetes NO bioavailability, 326–330 regulation, eNOS, 330–334 Dilated cardiomyopathy (DCM), 397–398 Dopamine (DA) release, 101–102 E EDRF See Endothelium-derived relaxing factor (EDRF) EMT See Epithelial-mesenchymal transition (EMT) Endothelial nitric oxide synthase (eNOS) See also Cardiovascular disease (CVD) antiobesogenic role (see Antiobesogenic role, eNOS) in cardiovascular homeostasis, 388 in endothelial cells, 388 gene–disease association network, 389, 389f gene polymorphisms (see eNOS polymorphisms) genetic variations Glu298Asp variants, 391 intron VNTR variant, 391–392 –786T/C variant, 391 hypoxia in vivo models, 182–184 posttranscription regulation, 181f, 182 transcription regulation, 180–182 protein synthesizes, 388 428 Endothelium-derived relaxing factor (EDRF) description, 80 glutamate, 86–87 L-arginine (L-Arg), 80–81 tumoricidal and bactericidal actions, 80–81 eNOS polymorphisms atrial fibrillation (AF), 397–398 cancer, 399 coronary artery disease and myocardial infarction endothelial dysfunction, 392–394 Glu298Asp polymorphism, 392–394 haplotype distribution, 392–394, 394t homozygosity, 392–394 NOS3 gene, 392–394 risk variants, 392–394, 394t T allele, 392–394 dilated cardiomyopathy (DCM), 397–398 hypertension, 394–396 ischemic stroke (IS), 396 metabolic disorders, 398–399 migraine, 400 pre-eclampsia (PE), 396 systemic lupus erythematosus, 400 eNOS uncoupling, 410 Epigenetics description, 284–285 free radicals, 284–285 JmjC demethylases, 285 pleiotropic nature %NO signaling, 285–286, 286f Epithelial-mesenchymal transition (EMT) in vivo model systems, 282 matrix metalloproteinases (MMP), 282, 283–284 %NO, metastasis, 282, 283 Snail activation, 281–282 ERK1/2 modulation by NO, 91 Estradiol antiapoptotic effects, 257–259 induced Akt and Erk activation, osteocytes, 257 NOS1 isoform, 250 osteoblasts and osteocytes, apoptosis, 250 PKG isoforms, apoptosis protection, 256 Index Estrogen antiapoptotic effects, 255–256 bone-protective effects, 249–250 interleukin-6 production, immune cells, 249 osteoclast apoptosis, 249 osteocyte apoptosis, 249–250 induction, NO synthesis, 250 “nongenomic” effects, 250 osteocyte survival, 254–259 eukaryotic Elongation Factor-2 Kinase (eEF2K), 88 G γ-aminobutryic acid (GABA) cGMP, 100–101 hippocampus/retina, 101 mechanism, 101 NMDA, 100–101 Glutamate AMPA and NMDA receptors, 10 glial cells, 100 L-arginine, 10 metabotropic receptors (mGluR), 98–99 N-ethylmaleimide (NEM), 10 Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 216 H Heart acute hypoxia and ischemia/ reperfusion “complex I syndrome”, 49 hypovolemic shock, 49–50, 50f in vitro model, 48–49 malate and glutamate, O2 consumption, 49 peroxynitrite, 48–49 restoration, blood flow, 48 Heart mitochondrial nitric oxide synthase (mtNOS) acute hypoxia and ischemia/reperfusion, 48–50 Ca2+ uptake, 43 cell injury and death, 44 cGMP-independent pathways, 40 chronic hypoxia, 47–48 citric acid/Kreb’s cycle, 37f, 41 EDRF, 30–31 eNOS, nNOS and iNOS, 31 429 Index metabolic state and membrane potential, 38–39 mitochondrial biogenesis, 43–44 nitrosation reactions, 40–41 NO production cardiomyocytes, 31–32 confocal microscopy, 32 gold particles, 35 immunochemical detection, 34–35, 34t MALDI-TOF, rat liver, 35 membrane potential, 32–33 methods, 32, 33t O2 consumption and H2O2 production, 34 porphyrinic microsensor, 35 silver enhanced gold immunolabelling method, 32 O2 uptake and H2O2 production, 44–47, 46f oxidative phosphorylation, 30, 43 peroxynitrite, 41 physiological conditions, 30 reactive oxygen species, 42 reversible inhibition, S-nitrosation, 42–43 soluble guanylate cyclase (sGC), 40 substrates and cofactors effect, 36–38, 37f Heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1), 182 HIF See Hypoxia-inducible factor (HIF) High voltage-activated calcium channels (HVACCs), 11, 13f Hippocampus and NO in CNS disorders, 142–149 NO diffusion, 131 NO formation, 130–131 NO metabolism, 131–132 NO signaling, 132–133 intractable epilepsy, 129–130 LTP, 134–136 neurogenesis, 136–139 nitrites and nitrates, 128–129 signaling nitrate tyrosine residues, 133 peroxynitrite-dependent cytotoxicity, 132–133 sGC activation, 132 S-nitrosylation, 133 subdivisions, 129 synaptogenesis, 139–142 hnRNP E1 See Heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) 5-HT See 5-Hydroxytryptamine (5-HT) Human inducible nitric oxide synthase (iNOS) gene posttranscriptional regulation, 21 transcriptional regulation, 20–21 HVACCs See High voltage-activated calcium channels (HVACCs) 5-Hydroxytryptamine (5-HT), 102 Hypertension, 394–396 Hypovolemic shock, 49–50, 50f Hypoxia and anemia (see Anemia) endothelial NOS (eNOS), 180–182 HIF (see Hypoxia-inducible factor (HIF)) inducible NOS (iNOS), 179–180 nerve cells, 97–98 neuronal NOS (nNOS), 177–179 nitrosothiol synthases, 165–166 NO biology, S-nitrosylation and equilibrium, 165–166 O2 dependency, NOS enzymes, 184–185 SNO products and physiology, 166–167 Src activity, 92 Tibetan highlanders and genetic evolution, 163–164 Hypoxia-inducible factor (HIF) blood oxygen content, 172–174, 173f blood vessel growth and Hgb production, 167–168 description, 162 dysregulated expression, 168–170 GSNOR-deficient mice, 174 iNOS expression, 179–180 mitochondrial cytochrome c oxidase, 171 nNOS (– / –) mice, 171–172 O2 availability, 167–168, 169f and S-nitrosylation, 170 von Hippel–Lindau syndrome, 168–170 I Inducible nitric oxide synthase (iNOS) heart mtNOS, 31 430 Inducible nitric oxide synthase (iNOS) (Continued ) human inducible nitric oxide synthase (iNOS) gene, 20–21 hypoxia-inducible factor (HIF), 179–180 isoforms, 64–65, 67–68, 353–354 neurogenesis, inhibition, 138 NO, mechanisms of action, 310f NOS2/NO system (see NOS2/NO system) Inhaled NO, PH acute lung injury, 418 adult respiratory distress syndrome, 418 on arterial oxygenation, 416 bronchopulmonary dysplasia, 417–418 chronic obstructive pulmonary disease (COPD), 418–419 on PAP, 415–416 physiological effect, 415 PPHN, 416–417 pulmonary hypertensive crisis, 418 vasoreactivity, 414 Interferon gamma (IFNγ) cytostatic/cytotoxic and antitumor functions, 302–303 in human models, 302–303 IFNγ-induced NO, RCC, 310–315 in mouse models, 302–303 production, 302–303 signaling pathway toward NO production, 306f transcription genes, 302–303 Ischemia eNOS-deficient mice, 144 excitotoxicity, 142 nNOS inhibitors, 143–144 PARP activation, 143 peroxynitrite formation, 142–143 PSD-95, 144 stroke, 142 treatment, 144 Ischemic stroke (IS), 396–397 K KATP channels, Index L L-Arginine (L-Arg) arginase ARG2, 305–306 cytosolic ARG1, 305–306 endogenous synthesis, 305–306 ODC pathway, 305–306, 306f metabolism, 304f NOS/NO “arginine paradox”, 306–307 citrulline, 306–307 isoenzymes, 306–307 levels, in endothelial cells and macrophages, 306–307 Long-term potentiation (LTP) CA1 neuron, 134–135 cellular mechanisms, 134 dibutyrul cGMP, 136 domains, 135–136 high-frequency stimulation, cGMP, 135 L-methyl-arginine (L-Me-Arg), 135 postsynaptic cells, 134 M MCAO See Middle cerebral artery occlusion (MCAO) Metabolic disorders, eNOS polymorphisms, 398–399 microRNAs (miRNAs) hepatocytes, macrophages and cardiac myocytes, 22 human iNOS gene, 23, 24t miR-939, 22–24 miR-146a, 23–24 Middle cerebral artery occlusion (MCAO), 69–70 Migraine, 400 miR-939, 22–23 Mood disorders anxiety, 146 depression, 145–146 hippocampus, 145 sex difference, behaviors, 146–147 mtNOS activity, heart, 32–34 mtNOS identity, heart, 34–36 Index N Necrosis apoptosis and, 70–72, 96–97 ATP depletion, 132–133 Nervous system, NO classical actions cGMP levels, 83 NMDA-type glutamate receptors, 85, 86f sGC, 83, 84 S-nitrosylation, 84–85 and neuronal viability, 93–98 neuroplasticity (see Neuroplasticity) neurotransmitters release DA, 101–102 GABA, 100–101 glutamate, 98–100 5-HT, 102 serotonin, 102 signaling pathways AKT, 89–91 CREB, 92 ERK1/2, 91 PKG, 88–89 Src activity, 91–92 Neurogenesis cell proliferation, 137 CREB phosphorylation, 138 cultured NSCs, 137 DETA/NONOate, 137 eNOS gene, 138 iNOS inhibition, 138 7-nitroindazole (7-NI), 137–138 NSCs proliferation and differentiation, 138–139 progenitor cells, 136 regulatory factors, 136–137 synaptic plasticity, 136 Neuronal NOS (nNOS) anemia vs hypoxia, 171–172 heart mitochondrial nitric oxide synthase (mtNOS), 31 histochemical marker, 364–366 inhibitors, 143–144 inhibitor, systemic administration, 363 prostaglandin regulation, 234 431 Neuropeptide Y (NPY) intracellular mechanisms, 66–67, 68f live-cell imaging, 66 MCAO stroke model, 69–70 NO–cGMP–PKG signaling pathway, 66–67 physiological processes, 65–66 proliferative effect, 66, 68–69 retinal neural cells, 65–66 Neuroplasticity astrocyte-secreted factors, 107–108 cerebral cortex, 109–110 climbing fibers, Purkinje cells and parallel fibers, 110 developmental stages, 106 glial cells, 105–106, 107–108 growth processes, 106–107 LTP and LTD, 108–109 mechanisms, 103–105, 104f monocular enucleation, adult rats, 105–106 neocortical neurons, 109–110 presynaptic neurons and postsynaptic cells, 105–106, 107 retinocolicular system, 110–111 RVLM neurons, 110 synaptopathy, 103 Neurovascular coupling (NVC) in anesthetized mice, 360–362 arterial dilation to AMPA, 367 catecholamines circulation, 362–363 CBF control, NO interneurons, 365f cerebellar Purkinje cells, 369 c-Fos expression analysis, 367 eNOS role, 363 hemodynamic response, 366–367 ionotropic receptors activation, 363–364 maintenance, 363–364 MK-801, selective NMDA receptor antagonist, 366–367 NADPHd, nNOS histochemical marker, 364–366 neuropeptide (NP)Y interneurons, 364–366 nitrergic interneurons, 368–369 NOS inhibition, 363 NOS interneuron, 367–368 in unanesthetized animals, 362–363 432 Neurovascular coupling (NVC) (Continued ) vascular smooth muscle cells, 361f vasoactive intestinal peptide (VIP) interneurons, 364–366 vasomotor control, 368–369 Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPHd), 364–366 Nitric oxide (NO) antiproliferative effect, 59–60 bone-anabolic effects, humans, 253–254 and cancer (see Cancer) cellular bioenergetics regulation (see Heart mitochondrial nitric oxide synthase (mtNOS)) cellular reactions, 267–288 and cerebrovascular regulation (see Cerebrovascular regulation) genetic polymorphisms in CVD (see Endothelial nitric oxide synthase (eNOS)) hippocampus and (see Hippocampus and NO) homeostasis and cytotoxicity, 214–215 human iNOS gene, regulation, 20–21 hypoxia signaling (see Hypoxia) IFNγ-induced (see NOS2/NO system) L-arginine (L-Arg) metabolism, 305–307 miRNAs regulation, 21–24 in nervous system (see Nervous system, NO) neurogenesis, adult (see Adult neurogenesis) in neurovascular coupling (NVC), 360–362, 361f nitric oxide synthase (NOS) types, 300–301 NO/cGMP signaling, bone cells, 251–253 nociceptive transduction and transmission (see Nociceptors) osteocyte survival, NO/cGMP/PKG pathway, 254–259 peroxynitrite-mediated reaction, 217 proapoptotic cyt c–CL complex binding (see Cytochrome c-cardiolipin complex and NO binding) Index prostaglandin regulation (see Prostaglandin regulation) in pulmonary hypertension (see Pulmonary hypertension (PH)) redox-related species, 213–214 smooth muscle relaxation, 370 S-nitrosylation, 215–216 sources, in neurovascular unit, 349–350 synthesis, estrogen, 250, 251f Nitric oxide synthase (NOS) Ca2+–calmodulin, 82 and cancer, 278–280 chronic treatment, inhibitors, 331 and COX2 activity, 228–229 EDRF, 80–81 expression, tumor, 277–278 human platelets, 229–230 hypoxia, 277–278 isoforms, 266, 271–272, 325 isozymes, 213 mitochondrial, 213 nitrate–nitrite–nitric oxide pathway, 81 NO production, 231–232 oxygenase and reductase domain, 213 prostaglandin production, 229 protein kinases, phosphorylation, 82–83 purification and cloning, rat cerebellum, 80–81 serum triglycerides and fatty acid, 332–334 tissue distribution and expression pattern, 82 Nitrogen monoxide (%NO) See also Nitric oxide (NO) cellular reactions and cancer (see Cancer) chemical biology, %NO signaling, 268f CIP, 270 direct and indirect reactions, 268f, 270–271 local oxygen concentration, 271–272 metabolism, 273 3-NT, 269 O2 reaction, 272 S-nitrosothiols (RSNO) formation, 267–269 tissue oxygen gradient, 271–272 433 Index in NOS expression, 266–267 in signal transduction pathways, 266 NMDA receptors cGMP levels, glutamate, 86–87 eEF2K, 88 LTP, 85–86 PSD-95, 87–88 nNOS See Neuronal NOS (nNOS) NO bioavailability, in obese and diabetic states Akt-eNOS pathway, 327–328 blood flow and shear stress, 329–330 caveolin-1 upregulation, 327 ceramide, 327 cofactor BH4, 328–329 elevated free fatty acids (FFAs), 328 endothelial dysfunction, 329–330 enzyme coupling, 328–329 insulin resistance initiation, 327 in mice, 327–328 mRNA stability, 327 3-nitrotyrosine (3-NT) modifications, 329 peripheral tissues, nutrient disposition, 327–328 phosphorylation, 327–328 postprandial blood flow, 327–328 Nociceptors activation, ASIC, description, KATP channels, transduction L-NAME, paravascular tissues and veins, 3–4 sGC-knockout mice, S-nitroso-N-acetylpenicillamine (SNAP), 4–5 transdermal nitroglycerine, 3–4 transmission analgesic effect, morphine, 8-bromo-cGMP, L-arginine, doses, 7-nitroindazole/L-NAME, 7, 8–9 NMDA receptor activation, TRP channels, 5–7 NOS See Nitric oxide synthase (NOS) NOS2 See Inducible nitric oxide synthase (iNOS) NOS3 See Endothelial nitric oxide synthase (eNOS) NOS2/NO system L-Arg (see L-Arginine (L-Arg)) bacterial pathogens L-Arg metabolism, 307–308 mycobacterial growth, 308 Mycobacterium tuberculosis infection, murine model, 308 NOS2 knockout mice, 307–308 NO synthase inhibitors (L-NMMA), 307–308 pathogenesis, 307–308 reactive nitrogen intermediates, 307–308 resident phagocytes, 307–308 cancer in antimicrobial immunity, 308–309 antitumor effects mechanisms, 308–309 antitumor responses, reestablishment, 309–310 macrophages role, 308–309 NO production, in tumor microenvironment, 309–310 in tumor cells, 308–309 expression, 303–304 inflammation and infection, 303–304 intermediate Nω-hydroxy-L-arginine (NOHA), 303–304 JAK/STAT pathways, 303–304 JNK-kinases, 303–304 omnipresent intercellular messenger, 304–305 superoxide, 304–305 transcription, 303–304 NPY See Neuropeptide Y (NPY) O Obesity and insulin resistance, regulation, 330–334 antiobesogenic phenotype, 332 beraprost, 330–331 erectile dysfunction in humans, 330–331 genetic models, 331 in hepatocytes, 332–334 434 Obesity and insulin resistance, regulation (Continued ) high-fat feeding mice, 333f immunoblot analysis, 333f l-arginine supplementation, 330 lipid oxidation/synthesis, 332–334 NOS inhibitors, chronic treatment, 331 overexpressing mice, 332, 333f peroxisome proliferator activated receptor (PPAR)-α, 332–334 phosphomimetic point mutant mouse model, 332 sildenafil, 330–331 in skeletal muscle, 332–334 S-nitrosation, 330–331 substrate metabolism, 332 TG mice, fat diet, 333f Osteoblasts antiapoptotic effects, estrogen, 255–256 17β-estradiol, 250, 252f NO production, estrogens, 250, 253 PKG I and II, 253 Osteocytes apoptosis, 249–250, 257–258 17β-estradiol, 250, 252f estrogen effects (see Estrogen) PKG I and II, 253 survival, estrogen promotion, 254–259 viability, 249–250 Osteoporosis American women, 248 anabolic therapy, 248–249 Caucasian wome, 248 isosorbide mononitrate (ISMN), 254 postmenopausal, 248–249 treatment, 248–249 Oxidative/nitrosative stress, 133 Oxygen-sensing pathways, hypoxia, 163–164 P PARP See Poly(ADP-ribose) polymerase (PARP) Persistent pulmonary hypertension of the neonate (PPHN), 416–417 Phosphatase and tensin homolog (PTEN), 94–95 PKG modulation by NO, 88–89 Index Polyamines ARG-dependent synthesis, 310–311 cell proliferation, 304f, 311–313 ornithine decarboxylase (ODC), 300–301, 305–306 synthesis, 300–301, 308–309 Poly(ADP-ribose) polymerase (PARP), 132–133, 143 Postsynaptic density protein-95 (PSD-95) 8-Br-cGMP, 140–141 CAPON, 87–88 dendritic spines, 140–141 NMDAR and nNOS, 144 NOS I-coupled NMDA receptor, 85, 86f PPHN See Persistent pulmonary hypertension of the neonate (PPHN) Pre-eclampsia (PE), 396 Prostaglandin regulation bone metabolism and fracture healing, 226–228 cancer, 224–225 cardiovascular, 225–226 COX inactivation, 229 human platelets, 229–230 in vitro studies, 228–229 nervous system, 223–224 NOS and COX2 activity, 228–229 peroxynitrite-mediated apoCOX1, 231–232 binding sites, 230 Fe, heme moiety of COX, 232 holoCOX1, 231–232 prostacyclin synthase (PGCI), 232 SIN-1, 231 tyrosine residue modification, 231 posttranslational modifications, 230 S-nitrosylation, COX Cys523, 233–234 Cys313/Cys540 mutation, 233 nNOS and COX2 physical interaction, 234 SNAP, 233 thermogenesis and metabolism, 226 PSD-95 See Postsynaptic density protein-95 (PSD-95) PTEN See Phosphatase and tensin homolog (PTEN) 435 Index Pulmonary hypertension (PH) delivery in clinical use, 415 inhaled NO on arterial oxygenation, 416 on PAP, 415–416 physiological effect, 415 NO-related relaxation responses, 414 in vascular basal tone, 412 vasoreactivity hypoxic PH, 413 MCT-induced PH, 413–414 NO inhalation, 414 in vasorelaxation and proliferation bone morphogenetic protein receptor type II and eNOS, 411–412 caveolin-1 and eNOS uncoupling, 411 eNOS expression and its activity, 410–412 eNOS uncoupling, 410 vascular endothelial growth factor and eNOS expression, 412 Pulmonary hypertensive crisis, 418 R Reactive nitrogen species, 93 Renal cell cancer (RCC), IFNγ-induced NO cyclins and/or cyclin-dependent kinases, 313–314 cytostatic role, 311–313 defective JAK/STAT signaling pathways, 313–314 in vitro mechanism, 313–314 immunomodulatory activity, 310–311 inhibitory cytokines, 314 L-Arg metabolism and cytokine production, 311–313 monotherapy, 311–313 murine kidney cancer cell lines, 311–313 polyamines, ARG-dependent synthesis, 310–311 in Renca cells, 314 signal transducer, 311–313 Th1 to Th2 cytokine response, 310–311 translational inhibition, 313–314 tumor microenvironment, 313–314 Resting CBF acute NOS blockade, 352 cavtratin complexes, 354 cGMP effect, 352–353 endogenous NOS inhibition, 350, 352 exogenous NO, 351 in humans, 351–352 3-morpholinosydnonimine (Sin-1), in vivo, 352–353 7-NI, in vivo administration, 353–354 nonselective NOS inhibitors, 350–351, 352 NO role, 350 in primates, 351–352 shear stress, 356–357 in transgenic mice, 354–355 vasomotion, 355–356 Retinocolicular LTD, 110–111 RNA binding proteins (RNA-BP), 21, 25 Rostral ventrolateral medulla (RVLM) neurons, 110 S SGZ See Subgranular zone (SGZ) S-Nitrosylation COX, 233–234 GAPDH, 216 hemoglobin, 216 NO+ production, 215 p21ras, 216 ryanodine receptor, 215–216 Spinal cords, synaptic transmission glutamatergic input, primary afferent nerves, 10 glycine, 11–12 HVACCs, 11 NMDA receptors, 11 nociceptive transmission, Src modulation by NO, 91–92 Subgranular zone (SGZ) BrdU+ cells, 69–70 dentate gyrus, 60–61, 61f DETA/NONOate, 64 eNOS-derived NO, 64–65, 65f 7-nitroindazole, 63–64 Subventricular zone (SVZ) BrdU and PSA-NCAM-positive precursors, 62–63 DETA/NONOate, 64 eNOS-derived NO, 64–65, 65f 436 Subventricular zone (SVZ) (Continued ) lateral ventricles, 60, 61f 7-nitroindazole, 63–64 rostral migratory stream, 60–61 Synaptogenesis hypoglossal axonal injury, 141–142 neurites outgrowth, 141 NMDA receptors, 139–140 nNOS155, 139 PSD-95, 140–141 synapse formation, 139 synapsin I, 141 Synaptopathy, 103 Systemic lupus erythematosus (SLE), 400 T Transient receptor potential (TRP) channels TRPA1, TRPV1, 5–6 TRPV3 and TRPV4, 6–7 Trans-nitrosylation, 213–214 TRP channels See Transient receptor potential (TRP) channels Index Tuberculosis See NOS2/NO system Tyrosine nitration, 94, 217 V Vascular and metabolic function, eNOS Ca2+ and calmodulin, 325 cyclic GMP (cGMP), 325 endothelial-derived relaxing factor (EDRF), 325 glutathione and proteins, cysteinyl thiols, 326 mitochondrial biogenesis, 326 neurons, epithelial cells, and cardiomyocytes, 325 NOS isoform, 325 oxygen delivery, 326 smooth muscle, acetylcholine-induced relaxation, 325 soluble guanylate cyclase (sGC), 325 superoxide, 326 vessel relaxation, 325 Vasomotion, 355–356 von Hippel–Lindau syndrome, 168–170 ... stimulating with a Vitamins and Hormones, Volume 96 ISSN 0083-6729 http://dx.doi.org/10.1016/B978-0-12-800254-4.00002-7 # 2014 Elsevier Inc All rights reserved 19 20 Zhong Guo and David A Geller... voltageactivated calcium channels NO also promotes synaptic glycine release from inhibitory Vitamins and Hormones, Volume 96 ISSN 0083-6729 http://dx.doi.org/10.1016/B978-0-12-800254-4.00001-5 # 2014 Elsevier... Campello-Costa, and R Paes-de-Carvalho Y Hu and D.-Y Zhu report on “Hippocampus and nitric oxide.” “Nitric oxide and hypoxia signaling” is a review by H.S.J Man, A.K.Y Tsui, and P.A Marsden M.A