Atherosclerosis and Oxidant Stress: A New Perspective

Preface

Contents

Contributors

The Pathogenesis of Atherosclerosis and Plaque Instability

Creation of the Lipid Core

Local Inflammation in the Vessel Wall

Thinning of the Fibrous Cap

References

Epidemiological Studies on Atherosclerosis: The Role of the Mediterranean Diet in the Prevention of Cardiovascular Disease

Introduction

The Mediterranean Diet and Risk of CVD

Observational Study Results

Clinical Trial Results – Variations to the Mediterranean Diet

The Lyon Diet Heart Study

Indo-Mediterranean Diet Heart Study

Clinical Feeding Study Results

The Dash Trials

OMNI Heart Trial

Mediterranean Diet Effects on Oxidative Stress

Summary and Conclusion

References

Interventional Trials of Antioxidants

Introduction

Basic Laboratory Research

Observational Epidemiology

Rationale for Randomized Trials

Vitamin E Primary Prevention Trials

Vitamin E Secondary Prevention Trials

Beta-carotene Primary Prevention Trials

Beta-carotene Secondary Prevention Trials

Vitamin C Trials

Combination Antioxidant Primary Prevention Trials

Combination Antioxidant Secondary Prevention Trials

Conclusions

Recommendations

References

Oxidative stress and Hypertension

Introduction

The Paradigm of Oxidative Stress: Reduction– Oxidation Concepts

Vascular Production of Reactive Oxygen Species

Vascular NAD(P)H Oxidases

Uncoupling of NOS

Vascular Antioxidant Defense Systems

Molecular Targets of Reactive Oxygen Species in Vascular Cells

Transcription Factors

Protein Tyrosine Phosphatases

Protein Tyrosine Kinases (PTK)

Mitogen-Activated Protein Kinases

Cation Transport Systems

Vascular Mechanisms of Oxidative Stress in Hypertension

Reactive Oxygen Species Influence Vascular Structure and are Pro-inflammatory

Reactive Oxygen Species Reduce NO Bioavailability

Reactive Oxygen Species in Hypertension

Oxidative Stress in Experimental Models of Hypertension

Oxidative Stress in Human Hypertension

Therapeutic Potential of Altering Bioavailability of Reactive Oxygen Species

Conclusions

References

Lipids, Oxidation, and Cardiovascular Disease

The Impact of Cardiovascular Disease and Its Major Component, Coronary Heart Disease on Human Health

Blood Lipids and Coronary Heart Disease

The Influence of Dietary Fats on Blood Cholesterol Levels and Distribution of Fatty Acids

The Pathogenesis of Coronary Heart Disease

Oxidized Lipids and Atherosclerosis

Mitochondria, Oxidative Stress, and Bioactive Lipids: A New Concept

Controlled Release of Reactive Oxygen Species for Mitochondria and Cellular Redox Signaling Pathways

Pathways Influenced by Mitochondrial ROS and Oxidized Lipids

Oxidized LDL, Signal Transduction Pathways, and Protection of Vascular Cells

Summary

References

Nuclear Receptors in the Control of Lipid Metabolism

The Nuclear Receptor Superfamily

Class I Receptors – the Classic Nuclear Hormone Receptors

Class II – the Metabolic Sensors

Class III and Class IV – the Orphans

Nuclear Receptors as Potential Therapeutic Targets for Metabolic Diseases

Conclusion

References

Diabetes and Oxidant Stress

Definition and Prevalence of Diabetes

Chronic Complications of Diabetes and Risk Factors

Definition and Mechanisms of Oxidative Stress

Measurement of Oxidative Stress

Is Oxidative Stress per se Increased in Diabetes and Vascular Damage?

The Link Between Oxidative Stress and Vascular Damage in Diabetes

Treatment of Oxidative Stress

Conclusion and Future Directions

References

Molecular Mechanisms of Environmental Atherogenesis

Epidemiology of Cardiovascular Disease

Atherosclerosis

Response to Injury Hypothesis

Clonal Expansion Hypothesis

Pathogenesis of Atherosclerosis

Environmental Risk Factors

Atherogens vs. Carcinogens

Reactive Oxygen Species and Oxidative Stress

Cellular Redox Reactions

Redox Cycling

Reactive Oxygen Species and Atherosclerosis

Reactive Oxygen Species as Second Messengers

Reactive Oxygen Species as Protein Modifiers and Phosphorylation Mediators

Benzo[a]pyrene

Bay Region Hypothesis

Metabolism of Benzo[a]pyrene, Enzyme Systems and Reactivity of Metabolites

Target Organs and Cellular Localization of Benzo[a]pyrene

Benzo[a]pyrene Carcinogenicity

Macromolecular Adduction

Benzo[a]pyrene and Atherosclerosis

Modulation of Gene Expression by Benzo[a]pyrene through the Aryl Hydrocarbon Receptor

c-Ha-ras

Signal Transduction through the Ras Pathway

c-Ha-ras and Atherosclerosis

c-Ha-ras and Benzo[a]pyrene

c-Ha-ras and Redox Signaling Pathways

Mitogenic Signaling Induced by Benzo[a]pyrene

Oxidant-Regulated Signaling in vSMCs

Antioxidant/Electrophile Response Element

Protein Binding to ARE/EpRE

Concluding Remarks

References

The Role of Glutathione Pathways in the Prevention of Atherosclerosis

The Role of Oxidized Serum Lipids in the Chronic Vascular Inflamation Associated with the Development of Atherosclerosis

Mechanisms for the Initiation of Vessel Injury by Oxidized Lipids

The Role of Antioxidant Systems in the Protection of the Vessel Wall from Oxidant Injury

The Correlation between the GSH and Cysteine Levels and Vascular Disease

The Selenium Dependent GSH-Peroxidases and Paraoxonases

The Role of GPx1 in the Prevention of Vascular Injury

The Role of GPx3 in the Prevention of Vascular Disease

The Role of the Gluthathione S-Transferases Polymorphinsms in the Development of Vascular Disease

Effect of Ischemic Heart Disease, Diabetes Mellitus and Chronic Renal Failure on the GSH Peroxidases

Ischemic Heart Disease

Diabetes Mellitus

The Effect of Renal Failure on the Antioxidant Pathways

The Effect of Drugs on the GSH Dependent Pathways

Hormone Replacement Therapy

Statins and Fibrates

Conclusions

References

Index