Nitric Oxide (eBook)

Front Cover 1
Nitric Oxide: Biology and Pathobiology 4
Copyright Page 5
Contents 6
Section I. Chemical Biology 8
Chapter 1 Determinants of Nitric Oxide Chemistry: Impact of Cell Signaling Processes 10
ABSTRACT 10
INTRODUCTION 10
CONTEXT DEPENDENCE OF NO RESPONSE 12
CELLULAR MILIEU AND NO REDOX CHEMISTRY 13
CONCENTRATION RANGE OF ENDOGENOUSLY GENERATED NO 14
KINETIC DETERMINANTS FOR MOLECULAR TARGET INTERACTIONS 18
CONCLUSION 25
REFERENCES 25
Chapter 2 Nitric Oxide Redox Biochemistry in Lipid Environments 34
SUMMARY 34
CHEMISTRY OF NITRIC OXIDE AND REACTIVE NITROGEN SPECIES 34
PHYSICAL INTERACTIONS OF NITRIC OXIDE AND REACTIVE NITROGEN SPECIES WITH LIPID MEMBRANES AND LIPOPROTEINS 36
REACTIONS OF REACTIVE NITROGEN SPECIES IN LIPID MILIEU 41
LIPID NITRATION AND ITS ROLE IN INFLAMMATION 51
CONCLUDING REMARKS 55
ACKNOWLEDGMENTS 56
REFERENCES 56
Chapter 3 Mechanisms and Biological Consequences of Peroxynitrite-Dependent Protein Oxidation and Nitration 68
SUMMARY 68
OVERVIEW OF PEROXYNITRITE BIOCHEMISTRY 69
PEROXYNITRITE-MEDIATED AMINO ACID AND PROTEIN MODIFICATIONS 70
BIOLOGICAL CONSEQUENCES OF PEROXYNITRITE-MEDIATED PROTEIN OXIDATION AND NITRATION 89
CONCLUSIONS 93
ACKNOWLEDGMENTS 93
REFERENCES 93
Chapter 4 Systems Approaches to Unraveling Nitric Oxide Response Networks in Prokaryotes 110
SUMMARY 110
INTRODUCTION 110
BIOLOGICAL CIRCUITS 111
RNS PRODUCTION AND INTERACTION WITH PROKARYOTES 112
RNS RESPONSE ELEMENTS 113
GLOBAL RNS RESPONSE 120
CLOSING REMARKS 131
REFERENCES 132
Section II. Principles of Biology 144
Chapter 5 Uncoupling of Endothelial Nitric Oxide Synthase in Cardiovascular Disease and its Pharmacological Reversal 146
SUMMARY 146
INTRODUCTION 147
NORMAL ENZYMATIC FUNCTION OF ENDOTHELIAL NO SYNTHASE ([sub(E)]NOS) 147
PHYSIOLOGIC REGULATION OF [sub(E)]NOS ACTIVITY 149
OXIDATIVE STRESS IN VASCULAR DISEASE REDUCES THE BIOAVAILABILITY OF VASCULAR NO 150
CARDIOVASCULAR RISK FACTORS AND VASCULAR DISEASE ARE ASSOCIATED WITH AN INCREASED PRODUCTION OF ROS IN THE VASCULAR WALL 150
ANTIOXIDANT ENZYMES POTENTIALLY PROTECTING AGAINST VASCULAR OXIDATIVE STRESS 154
MOLECULAR MECHANISMS CONTRIBUTING TO REDUCED LEVELS OF BIOACTIVE NO IN VASCULAR DISEASE 156
MOLECULAR MECHANISMS TRIGGERING [sub(E)]NOS UNCOUPLING 156
VASCULAR OXIDATIVE STRESS AND ENDOTHELIAL DYSFUNCTION PREDISPOSE TO ATHEROSCLEROSIS 159
PHARMACOLOGICAL APPROACHES TO REDUCE OXIDATIVE STRESS AND PREVENT OR REVERSE [sub(E)]NOS UNCOUPLING 159
CONCLUSIONS 161
REFERENCES 162
Chapter 6 Tetrahydrobiopterin: An Essential Cofactor for Nitric Oxide Synthases and Amino Acid Hydroxylases 176
SUMMARY 176
FROM THE WINGS OF BUTTERFLIES TO HYDROXYLATING COFACTOR: DISCOVERY OF PTERINS 176
BH[sub(4)] IS AN ESSENTIAL COFACTOR FOR AAAHS AND NOSs 178
BH[sub(4)] REDOX PROPERTIES AND REGENERATION BY SALVAGE AND RECYCLING PATHWAYS 185
DE NOVO BIOSYNTHESIS OF BH[sub(4)] 186
ANATOMICAL AND SUBCELLULAR LOCALIZATION OF GTPCH 191
REGULATION OF GTPCH ACTIVITY 191
GENETIC DISEASES MEDIATED BY BH[sub(4)] DEFICIENCY 197
MOUSE MODELS OF BH[sub(4)] DEFICIENCY 200
ACKNOWLEDGMENT 201
REFERENCES 201
Chapter 7 Regulation of the Expression of Inducible Nitric Oxide Synthase 218
SUMMARY 218
INTRODUCTION 218
STRUCTURE OF THE HUMAN iNOS GENE 219
REGULATION OF iNOS ACTIVITY 220
EXPRESSIONAL REGULATION OF iNOS 220
CONCLUSIONS 248
REFERENCES 249
Chapter 8 Molecular Regulation of Inducible Nitric Oxide Synthase 276
INTRODUCTION 276
CLONING OF THE MURINE AND HUMAN INOS GENES 277
ANALYSIS OF THE MURINE AND HUMAN INOS PROMOTERS 278
A CENTRAL ROLE FOR THE NF-& #954
THE IFN/JAK/STAT PATHWAY CONTRIBUTES TO INOS INDUCTION 280
CYTOKINE SYNERGY REGULATES INOS TRANSCRIPTION 282
MAPK SIGNALING AND INOS 284
PI3K AND AKT SIGNALING EFFECTS ON INOS 284
AP-1 SIGNALING AND INOS TRANSCRIPTION 285
OCT-1 ALSO EXERTS EFFECTS ON INOS TRANSCRIPTION 285
EFFECTS OF CAMP, C/EBP, AND CAMP-RESPONSIVE ELEMENT BINDING PROTEIN (CREB) ON INOS EXPRESSION 286
iNOS IS A TARGET OF THE WNT/& #946
EPIGENETIC REGULATION OF THE HUMAN INOS GENE 288
POST-TRANSCRIPTIONAL REGULATION OF INOS EXPRESSION 289
AGENTS THAT DOWN-REGULATE INOS EXPRESSION 291
iNOS EXPRESSION IS NEGATIVELY REGULATED BY NO 293
SUMMARY 294
REFERENCES 294
Chapter 9 Soluble Guanylate Cyclase: Allosteric Activation and Redox Regulation 308
SUMMARY 308
INTRODUCTION 308
PHYSIOLOGICAL ROLES AND PATHOLOGICAL DYSFUNCTION 309
ENZYME STRUCTURE 309
SUBCELLULAR LOCALIZATION 311
TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATION 311
ISSUES WITH THE THERAPEUTIC USE OF NO DONORS AS SGC ACTIVATORS 312
ALLOSTERIC SGC STIMULATION: NO-INDEPENDENT, HEME-DEPENDENT STIMULATORS 312
ALLOSTERIC SGC ACTIVATION: NO-INDEPENDENT, HEME-INDEPENDENT ACTIVATORS 315
THERAPEUTIC POTENTIAL OF ALLOSTERIC SGC 'STIMULATORS' AND 'ACTIVATORS' (I.E. SGC AGONISTS) 316
CLINICAL TRIALS OF SGC AGONISTS 318
REDOX REGULATION: THIOL-BASED MODULATION 319
REDOX REGULATION: HEME FUNCTIONALITY 320
FUTURE DIRECTION 320
REFERENCES 321
Chapter 10 Untargeted Discovery of Nitric Oxide-Modified Proteins 334
SUMMARY 334
DISCOVERY-BASED APPROACHES FOR IDENTIFYING NO-DEPENDENT PROTEIN MODIFICATIONS 334
PROTEIN S-NITROSYLATION 335
TYROSINE NITRATION 364
THE FUTURE OF PROTEOMIC STUDIES AND NO 390
ACKNOWLEDGMENTS 391
REFERENCES 391
Chapter 11 Fatty Acid Transduction of Nitric Oxide Signaling: Cyclooxygenases, Lipoxygenases and Nitro-Fatty Acids 398
SUMMARY 398
INTRODUCTION 399
NO REACTIONS IN LIPOPHILIC MILIEU 399
NO MODULATES ENZYMATIC LIPID OXIDATION 401
FATTY ACID NITRATION PRODUCTS ARISING FROM NO-DERIVED SPECIES 404
MECHANISMS OF NO[sub(2)]-FA-MEDIATED CELL SIGNALING 406
SUMMARY 410
REFERENCES 410
Chapter 12 Nitric Oxide Signaling in Vascular Cells is Regulated through CD47 by Thrombospondin-1 422
ABSTRACT 422
INTRODUCTION 423
NITRIC OXIDE 423
THROMBOSPONDIN-1 424
INHIBITION OF NO SIGNALING BY TSP1 426
CD47 MEDIATES INHIBITION OF NO/CGMP SIGNALING 428
INHIBITION OF NO/CGMP SIGNALING VIA CD36 428
TSP1 REGULATION OF NO SIGNALING IN PLATELETS 429
TSP1 AND WOUND HEALING 430
TSP1 MODULATES TISSUE BLOOD FLOW AND SURVIVAL UNDER VASOACTIVE AND ISCHEMIC STRESS 431
TSP1 AND DECREASED BLOOD FLOW IN AGING 433
TSP1 LIMITS TISSUE SURVIVAL TO ISCHEMIA-REPERFUSION INJURY 433
TARGETING TSP1 OR CD47 INCREASES TISSUE BLOOD FLOW AND SURVIVAL AFTER ISCHEMIA AND I/R INJURY 435
FUTURE DIRECTIONS 435
REFERENCES 437
Chapter 13 The Regulation of Cell Energetics and Mitochondrial Signaling by Nitric Oxide 448
SUMMARY 448
INTRODUCTION: MITOCHONDRIAL FUNCTION AND ITS REGULATION 449
REGULATION OF CYTOCHROME OXIDASE ACTIVITY AND MITOCHONDRIAL OXYGEN UPTAKE BY NO: O[sub(2)]/NO COMPETITION 450
SOURCES OF MITOCHONDRIAL NITRIC OXIDE 453
mtNOS: ACTIVITY, EXPRESSION AND INTERNALIZATION 453
THE REDUCTION OF NITRITE 457
THE MITOCHONDRIAL PRODUCTION OF SUPEROXIDE RADICAL AND OF HYDROGEN PEROXIDE 457
THE MITOCHONDRIAL PRODUCTION OF SUPEROXIDE RADICAL IS HIGHLY STIMULATED BY NO 458
MITOCHONDRIAL NO UTILIZATION 460
UBIQUINONE SUPPLEMENTATION: SOD PRODUCTION, NO DECAY AND REVERSION OF CYTOCHROME OXIDASE INHIBITION 460
PEROXYNITRITE-DEPENDENT PRODUCTION OF SOD 461
THE INTEGRAL MITOCHONDRIAL METABOLISM OF O[sub(2)], NO AND SOD 462
NO AND H[sub(2)]O[sub(2)] IN CELL FATE: MITOCHONDRIAL SIGNALING IN CELL PROLIFERATION, ARREST AND APOPTOSIS 465
THE REGULATION OF CELL ENERGETICS THROUGH MITOCHONDRIAL POPULATION 468
THE APPLIED PHYSIOLOGY OF MITOCHONDRIAL NO 469
NO, MITOCHONDRIA AND ENDOCRINE REGULATION 471
MITOCHONDRIAL NO CONCENTRATIONS AND MECHANISMS OF DISEASE 472
CONCLUDING REMARKS 476
ACKNOWLEDGMENTS 478
REFERENCES 478
Chapter 14 Nitric Oxide – Asymmetric Dimethylarginine System in Endothelial Cell Senescence 490
SUMMARY 490
INTRODUCTION 490
BIOMARKERS OF CELLULAR SENESCENCE 491
NO-ADMA SYSTEM IN ENDOTHELIAL CELL SENESCENCE 494
MODULATION OF NO-ADMA SYSTEM CONTRIBUTES TO DELAY OR ACCELERATION OF THE PROCESS OF HUMAN ENDOTHELIAL CELL SENESCENCE 501
CONCLUSIONS 506
REFERENCES 506
Chapter 15 The Role of Nitric Oxide in Apoptosis and Autophagy: Biochemical and Computational Studies 520
SUMMARY 520
INTRODUCTION 521
EFFECTS OF NO ON APOPTOSIS 522
NITRIC OXIDE MODULATES CELL DEATH-RELATED GENES 528
DECODING THE COMPLEX ROLES OF NO IN APOPTOSIS USING COMPUTATIONAL SIMULATIONS 531
CONCLUSION/NO APOPTOSIS AND AUTOPHAGY FUTURE MODELING 534
ACKNOWLEDGMENTS 534
REFERENCES 534
Chapter 16 Nitric Oxide Formation from Inorganic Nitrate and Nitrite 546
SUMMARY 546
INTRODUCTION 546
SOURCES OF NITRATE AND NITRITE 547
THE ENTEROSALIVARY CIRCULATION OF NITRATE 547
DIETARY NITRATE AND GASTRIC CANCER 548
INTRAGASTRIC GENERATION OF NITRIC OXIDE 549
INTERACTIONS BETWEEN NITRITE AND OTHER DIETARY COMPOUNDS 550
SYSTEMIC NO GENERATION FROM NITRITE 552
NITRITE AS A VASODILATOR 552
MECHANISMS FOR NITRITE REDUCTION 552
BIOACTIVATION OF INORGANIC NITRATE 553
DIETARY NITRATE AND NITRITE AND CARDIOVASCULAR FUNCTION 554
REFERENCES 555
Chapter 17 Mechanisms of Nitrite Reduction in Ischemia in the Cardiovascular System 562
SUMMARY 562
INTRODUCTION 562
SOURCE AND STORAGE OF ENDOGENOUS NITRITE 563
BIOLOGICAL ACTIVITY OF NITRITE: DEPENDENCY ON OXYGEN AND REDUCTION TO NO 566
EFFECTS OF NITRITE IN I/R INJURY 569
NON-ENZYMATIC CONVERSION OF NITRITE TO NO 572
ENZYMATIC CONVERSION OF NITRITE TO NO 573
THERAPEUTIC POTENTIAL OF NITRITE 581
REFERENCES 581
Chapter 18 Nitrite Therapy for Ischemic Syndromes 594
ABSTRACT 594
INTRODUCTION 595
NO AND PROTECTION AGAINST ISCHEMIA 595
NITRITE AND PROTECTION AGAINST ISCHEMIA/REPERFUSION INJURY 597
NITRITE AND THERAPEUTIC ANGIOGENESIS 601
FUTURE RESEARCH CONSIDERATIONS 602
CLINICAL TRANSLATION OF NITRITE THERAPY TO ISCHEMIC DISEASES 603
SUMMARY 605
CONFLICT OF INTEREST 606
REFERENCES 606
Chapter 19 Nitrite and Heme Globins: Reaction Mechanisms and Physiological Targets 612
SUMMARY 612
INTRODUCTION 612
SOURCES OF NITRITE IN VIVO 613
NITRITE AND HEME GLOBINS: A LONG HISTORY 613
NITRITE: A PHYSIOLOGICAL VASODILATOR OR INERT METABOLITE? 615
HEMOGLOBIN AND NITRITE: OLD CHEMISTRY REVISITED 615
ESCAPING HEME SCAVENGING: REDUCTIVE ANHYDRASE CHEMISTRY 618
OTHER REACTION PATHWAYS TO N[sub(2)]O[sub(3)] FORMATION 620
EXPANDING THE PARADIGM: MYOGLOBIN AS A TISSUE NITRITE REDUCTASE 620
NITRITE MEDIATES CYTOPROTECTION AFTER CARDIAC ISCHEMIA/REPERFUSION 622
MECHANISMS OF CYTOPROTECTION: MITOCHONDRIA AS A TARGET OF THE NITRITE–MYOGLOBIN REACTION 624
S-NITROSATION OF MITOCHONDRIAL COMPLEX I AND CYTOPROTECTION AFTER ISCHEMIA/REPERFUSION 626
NEUROGLOBIN AS A NITRITE REDUCTASE 627
CONCLUSION 627
REFERENCES 627
Section III. Principles of Pathobiology 634
Chapter 20 Nitric Oxide in Vascular Damage and Regeneration 636
SUMMARY 636
NITRIC OXIDE SIGNALING IN THE ARTERY WALL 636
NO IN VASCULAR DYSFUNCTION 639
NO AND RENOVASCULAR DISEASE 640
CLINICAL MEASUREMENTS OF ENDOTHELIAL FUNCTION 644
NOS COMPETITIVE INHIBITORS AND ATHEROSCLEROSIS 646
NOS KNOCKOUT MICE IN THE PATHOBIOLOGY OF NO AND ATHEROSCLEROSIS 647
NO AND OXIDATION-SENSITIVE MECHANISMS 649
ENOS POLYMORPHISMS 651
MOLECULAR MECHANISMS REGULATING ENOS 652
NO AND POLYPHENOLS 654
NO AND VASCULAR REGENERATION 656
CONCLUSIONS AND ROAD AHEAD 662
ACKNOWLEDGMENTS 662
REFERENCES 662
Chapter 21 Free Radicals as Atherosclerotic Risk in Relation to Nitric Oxide 680
ABSTRACT 680
ATHEROSCLEROSIS AND FREE RADICALS 680
FREE RADICALS AND THROMBOSIS FORMATION 684
EFFECT OF ROS AND NO ON CORONARY RISK FACTORS: DIABETES 684
EFFECT OF ROS AND NO ON CORONARY RISK FACTORS: SMOKING 686
EFFECT OF ROS AND NO ON CORONARY RISK FACTORS: MENOPAUSE AND SEX STEROIDS 686
THE CROSS-TALK OF NO AND FREE RADICAL, ESPECIALLY NADPH OXIDASE-DERIVED SUPEROXIDE 690
EFFECT OF ROS AND NO ON CORONARY RISK FACTORS: AGING 692
CROSS RELATION BETWEEN CORONARY RISK FACTORS AND NO 696
CONCLUDING REMARKS 700
ACKNOWLEDGMENT 700
REFERENCES 700
Chapter 22 The Role of Oxidative Stress in Endothelial Dysfunction and Vascular Inflammation 712
ABSTRACT 712
INTRODUCTION 712
THE EMERGING GLOBAL EPIDEMIC: ATHEROSCLEROSIS, DIABETES MELLITUS AND AGING 713
THE REVOLUTIONARY CONCEPTS OF VASCULAR BIOLOGY 714
THE ENDOTHELIUM AND VASCULAR HOMEOSTASIS 715
ENDOTHELIAL DYSFUNCTION, ATHEROSCLEROSIS AND VASCULAR INFLAMMATION 716
PATHOPHYSIOLOGICAL INSIGHTS 718
VASCULAR SOURCES OF OXIDATIVE STRESS 721
FINAL COMMON MOLECULAR PATHWAYS OF ATHEROSCLEROSIS, DIABETES AND AGING 729
ROS AND ATHEROSCLEROSIS 731
DIABETES 735
AGING 739
CONCLUSION 742
REFERENCES 742
Chapter 23 Nitric Oxide, Oxidative Stress, Immune Response and Critical Care 762
SUMMARY 762
INTRODUCTION 762
NO AND ENDOTHELIAL DYSFUNCTION 763
NO AND ISCHEMIA/REPERFUSION INJURY 764
NO AND SEPSIS 766
NO AND ALI/ARDS 768
REFERENCES 769
Chapter 24 Reactive Metabolites of Oxygen and Nitrogen in Liver Ischemia and Reperfusion Injury 780
ABSTRACT 780
INTRODUCTION 780
I/R INCREASES ROS PRODUCTION, DECREASES NO BIOAVAILABILITY AND ALTERS THE REDOX STATE OF THE LIVER: A RECIPE FOR DISASTER 782
MECHANISMS OF SUPEROXIDE-DEPENDENT TISSUE INJURY 785
ROLE OF LEUKOCYTES IN I/R INJURY 791
REGULATION OF I/R-INDUCED LIVER DAMAGE BY ENDOGENOUS NO 792
PROTECTION OF POST-ISCHEMIC LIVER BY eNOS-INDEPENDENT GENERATION OF NO 793
CONCLUDING REMARKS 795
REFERENCES 796
Chapter 25 Nitric Oxide in Airway Inflammation 802
ABSTRACT 802
INTRODUCTION 802
LOCALIZATION OF NO IN AIRWAYS 803
NO IN PATHOPHYSIOLOGY OF LUNG 803
NO AND SIGNAL TRANSDUCTION IN AIRWAYS 806
PEROXISOME PROLIFERATOR ACTIVATED RECEPTORS (PPARS) 807
NO AND OXIDATIVE STRESS IN AIRWAY 808
CONCLUSION AND FUTURE PERSPECTIVES 808
ACKNOWLEDGMENTS 809
REFERENCES 809
Chapter 26 Novel Therapeutic Applications of Nitric Oxide in the Inhibition of Tumor Malignancy and Reversal of Resistance 820
SUMMARY 820
INTRODUCTION 820
CHEMISTRY, CELLULAR SOURCE, BIOCHEMICAL ACTIVITIES MEDIATED BY NO, AND ROLE IN HEALTH AND DISEASE 822
THERAPEUTIC AND PREVENTIVE EFFECTS OF NO IN CANCER 823
CHEMOPREVENTIVE ROLE OF NO IN CANCER 824
DIRECT ANTI-TUMOR ROLE OF NO IN CANCER 824
SENSITIZING ACTIVITIES OF NO TO APOPTOSIS BY THERAPEUTICS 825
NO INHIBITS EMT AND METASTASIS 828
PRECLINICAL THERAPEUTIC EFFICACY OF NO IN CANCER 828
THERAPEUTIC EFFICACY OF NO IN CANCER PATIENTS 828
CONCLUDING REMARKS 829
ACKNOWLEDGMENTS 830
REFERENCES 830
Index 838
A 838
B 839
C 839
D 840
E 841
F 841
G 842
H 842
I 843
J 844
K 844
L 844
M 844
N 845
O 847
P 847
Q 849
R 849
S 849
T 850
U 851
V 851
W 851
X 851
Y 852
Z 852