Atherosclerosis and Oxidant Stress: A New Perspective (eBook)

Preface 5
Contents 6
Contributors 8
The Pathogenesis of Atherosclerosis and Plaque Instability 10
Creation of the Lipid Core 11
Local Inflammation in the Vessel Wall 13
Thinning of the Fibrous Cap 14
References 16
Epidemiological Studies on Atherosclerosis: The Role of the Mediterranean Diet in the Prevention of Cardiovascular Disease 20
Introduction 20
The Mediterranean Diet and Risk of CVD 21
Observational Study Results 21
Clinical Trial Results – Variations to the Mediterranean Diet 25
The Lyon Diet Heart Study 25
Indo-Mediterranean Diet Heart Study 26
Clinical Feeding Study Results 27
The Dash Trials 27
OMNI Heart Trial 28
Mediterranean Diet Effects on Oxidative Stress 29
Summary and Conclusion 31
References 32
Interventional Trials of Antioxidants 34
Introduction 34
Basic Laboratory Research 34
Observational Epidemiology 35
Rationale for Randomized Trials 37
Vitamin E Primary Prevention Trials 37
Vitamin E Secondary Prevention Trials 40
Beta-carotene Primary Prevention Trials 44
Beta-carotene Secondary Prevention Trials 47
Vitamin C Trials 49
Combination Antioxidant Primary Prevention Trials 49
Combination Antioxidant Secondary Prevention Trials 51
Conclusions 54
Recommendations 55
References 55
Oxidative stress and Hypertension 60
Introduction 60
The Paradigm of Oxidative Stress: Reduction– Oxidation Concepts 61
Vascular Production of Reactive Oxygen Species 63
Vascular NAD(P)H Oxidases 63
Uncoupling of NOS 66
Vascular Antioxidant Defense Systems 67
Molecular Targets of Reactive Oxygen Species in Vascular Cells 67
Transcription Factors 68
Protein Tyrosine Phosphatases 69
Protein Tyrosine Kinases (PTK) 69
Mitogen-Activated Protein Kinases 70
Cation Transport Systems 70
Vascular Mechanisms of Oxidative Stress in Hypertension 71
Reactive Oxygen Species Influence Vascular Structure and are Pro-inflammatory 71
Reactive Oxygen Species Reduce NO Bioavailability 71
Reactive Oxygen Species in Hypertension 72
Oxidative Stress in Experimental Models of Hypertension 72
Oxidative Stress in Human Hypertension 73
Therapeutic Potential of Altering Bioavailability of Reactive Oxygen Species 73
Conclusions 77
References 78
Lipids, Oxidation, and Cardiovascular Disease 88
The Impact of Cardiovascular Disease and Its Major Component, Coronary Heart Disease on Human Health 88
Blood Lipids and Coronary Heart Disease 89
The Influence of Dietary Fats on Blood Cholesterol Levels and Distribution of Fatty Acids 90
The Pathogenesis of Coronary Heart Disease 92
Oxidized Lipids and Atherosclerosis 94
Mitochondria, Oxidative Stress, and Bioactive Lipids: A New Concept 96
Controlled Release of Reactive Oxygen Species for Mitochondria and Cellular Redox Signaling Pathways 97
Pathways Influenced by Mitochondrial ROS and Oxidized Lipids 98
Oxidized LDL, Signal Transduction Pathways, and Protection of Vascular Cells 98
Summary 99
References 100
Nuclear Receptors in the Control of Lipid Metabolism 105
The Nuclear Receptor Superfamily 105
Class I Receptors – the Classic Nuclear Hormone Receptors 107
Class II – the Metabolic Sensors 109
Class III and Class IV – the Orphans 117
Nuclear Receptors as Potential Therapeutic Targets for Metabolic Diseases 118
Conclusion 120
References 120
Diabetes and Oxidant Stress 132
Definition and Prevalence of Diabetes 134
Chronic Complications of Diabetes and Risk Factors 134
Definition and Mechanisms of Oxidative Stress 136
Measurement of Oxidative Stress 137
Is Oxidative Stress per se Increased in Diabetes and Vascular Damage? 139
The Link Between Oxidative Stress and Vascular Damage in Diabetes 149
Treatment of Oxidative Stress 150
Conclusion and Future Directions 153
References 154
Molecular Mechanisms of Environmental Atherogenesis 168
Epidemiology of Cardiovascular Disease 168
Atherosclerosis 169
Response to Injury Hypothesis 169
Clonal Expansion Hypothesis 171
Pathogenesis of Atherosclerosis 172
Environmental Risk Factors 173
Atherogens vs. Carcinogens 176
Reactive Oxygen Species and Oxidative Stress 177
Cellular Redox Reactions 178
Redox Cycling 178
Reactive Oxygen Species and Atherosclerosis 179
Reactive Oxygen Species as Second Messengers 180
Reactive Oxygen Species as Protein Modifiers and Phosphorylation Mediators 181
Benzo[a]pyrene 182
Bay Region Hypothesis 182
Metabolism of Benzo[a]pyrene, Enzyme Systems and Reactivity of Metabolites 183
Target Organs and Cellular Localization of Benzo[a]pyrene 187
Benzo[a]pyrene Carcinogenicity 187
Macromolecular Adduction 189
Benzo[a]pyrene and Atherosclerosis 191
Modulation of Gene Expression by Benzo[a]pyrene through the Aryl Hydrocarbon Receptor 192
c-Ha-ras 194
Signal Transduction through the Ras Pathway 195
c-Ha-ras and Atherosclerosis 197
c-Ha-ras and Benzo[a]pyrene 198
c-Ha-ras and Redox Signaling Pathways 198
Mitogenic Signaling Induced by Benzo[a]pyrene 199
Oxidant-Regulated Signaling in vSMCs 200
Antioxidant/Electrophile Response Element 201
Protein Binding to ARE/EpRE 202
Concluding Remarks 203
References 204
The Role of Glutathione Pathways in the Prevention of Atherosclerosis 220
The Role of Oxidized Serum Lipids in the Chronic Vascular Inflamation Associated with the Development of Atherosclerosis 220
Mechanisms for the Initiation of Vessel Injury by Oxidized Lipids 221
The Role of Antioxidant Systems in the Protection of the Vessel Wall from Oxidant Injury 222
The Correlation between the GSH and Cysteine Levels and Vascular Disease 222
The Selenium Dependent GSH-Peroxidases and Paraoxonases 223
The Role of GPx1 in the Prevention of Vascular Injury 224
The Role of GPx3 in the Prevention of Vascular Disease 226
The Role of the Gluthathione S-Transferases Polymorphinsms in the Development of Vascular Disease 229
Effect of Ischemic Heart Disease, Diabetes Mellitus and Chronic Renal Failure on the GSH Peroxidases 232
Ischemic Heart Disease 232
Diabetes Mellitus 232
The Effect of Renal Failure on the Antioxidant Pathways 234
The Effect of Drugs on the GSH Dependent Pathways 234
Hormone Replacement Therapy 234
Statins and Fibrates 235
Conclusions 236
References 236
Index 249