Cardiovascular Signaling in Health and Disease

Description

This contributed volume focuses on cardiovascular diseases (CVDs), and explores the ways in which signaling mechanisms at the biochemical, molecular, and cellular levels in the blood vessels (vascular) and heart contribute to the underlying causes of development and progression of the CVDs. This volume covers unique topics such as oxidant signaling in vascular and heart diseases and health, cytoskeletal signaling in vascular health and disease, phospholipase signaling in CVDs, lipid signaling in vascular and myocardial health and diseases, and drug discovery in cellular signaling for cardiovascular diseases. This book assembles the most important discoveries made by leaders on the cellular signaling mechanisms operating behind the development and progression of life-threatening CVDs. It is an extremely useful resource for the investigators in the field of CVDs, and opens the discussion for further discovery of efficient management and effective treatment of the CVDs. Preface on the Current Trends in Cardiovascular Signaling in Health and Disease Calcium- and Stress-Dependent Signaling in Cardiac Myocytes Reactive Oxygen Species and Lipid Signaling in Cardiac Myocytes Inflammatory Signaling, Fibrosis, and Cardiac Function Neural Regulation of Cardiac Rhythm Reverse Cholesterol Transport in Atherosclerotic Cardiovascular Disease Progression of the Atherosclerotic Plaque Regression Role of Bioactive Lipid, Phosphatidic Acid in Statin-Induced Myotoxicity Cell-to-Cell Communication in the Vascular Endothelium The Bioactive Phospholipid, Lysophosphatidic Acid Regulates Vascular Endothelial Barrier Integrity Role of Lipid Mediators in Regulation of Vascular Endothelial Barrier Integrity and Function Role of Iron in Diabetic Vascular Endothelial Dysfunction Acknowledgments Contents Authors Biography Part I: Cardiac Signaling Calcium-Dependent Signaling in Cardiac Myocytes Introduction Physiology Pathophysiology Heart Failure Arrhythmias Ca-Dependent CaMKII Signaling in the Cardiac Myocyte Background Ca-Dependent CaMKII Signaling in Cardiac Myocyte Function and Disease CaMKII Structure and Ca-Dependent Activation Posttranslational Modifications of CaMKII as Novel Mechanisms of Cardiac Disease Cardiac Myocyte Remodeling and Ultrastructural Change Background Ultrastructural (T-Tubule) Remodeling RyR Remodeling Consequence of Structural Remodeling on Spatiotemporal Factors of Ca Release Potential Treatments Conclusions and Research Frontiers Spatial and Temporal Heterogeneity of Ca-Dependent Signaling Considerations for Therapy References Organization of Ca2+ Signaling Microdomains in Cardiac Myocytes Introduction Calcium Signaling in Cardiomyocytes Calcium Signaling Microdomains in Cardiomyocytes TT/jSR Microdomains in Systolic and Diastolic Calcium Handling Organization of cBIN1 and JP2 Microdomains at TT/jSR Membrane Calcium Signaling at the cBIN1 and Other TT/jSR Microdomains TT/jSR Microdomains, Calcium Signaling, and Heart Failure Ankyrin-Spectrin Microdomains in Calcium Signaling Organization of Ankyrin B-βII Spectrin Microdomains Ankyrin-Spectrin Microdomain-Regulated Calcium Signaling Ankyrin-Spectrin Microdomains in Cardiovascular Diseases Caveolae Microdomains in Calcium Signaling and Stress Response Organization of Caveolae Microdomains in Cardiomyocytes Caveolae-Related Organization of Calcium Signaling Caveolae, Calcium Signaling, and Disease Conclusions and Future Perspectives References Stress Kinase Signaling in Cardiac Myocytes Introduction Stress Kinase MAPK Signaling in the Heart JNK P38 ERK MAPKs and Calcium Homeostasis in Myocytes Normal and Abnormal Calcium (Ca2+) Signaling in Myocytes MAPKs in Stress-Evoked Ca2+ Mishandling in Myocytes MAPKs and Ca Handling Proteins in Myocytes MAPKs and Molecular Remodeling in Myocytes MAPKs and Gene Regulation in Myocytes MAPKs and Apoptotic Signaling Pathways in Stress-Exposed Myocytes JNK and Apoptotic Signaling Pathways in Myocytes p38 and Apoptotic Signaling Pathways in Myocytes ERK and Apoptotic Signaling Pathways in Myocytes Dynamic Relationships of MAPKs in Pathological Cardiac Remodeling in Stressed Hearts MAPKs and Therapeutic Potentials References Intracellular Cardiac Signaling Pathways Altered by Cancer Therapies Part I: Introduction Tyrosine Kinase Inhibitor Therapy Immune Checkpoint Therapy CAR T-Cell Therapy Part II: Tyrosine Kinases Inhibitor Therapy Tyrosine Kinase Signaling Abnormal Tyrosine Kinase Activity and Signaling in Cancer Tyrosine Kinase Inhibitors Tyrosine Kinase Receptors and Cardiomyopathy VEGF/VEGFR Signaling PDGF/ PDGFR Signaling c-KIT Signaling TKI-Induced Cardiovascular Dysfunction Hypertension Arrhythmias TKIs and Ion Homeostasis TKI-Mediated Potassium Ion Channel Dysfunction TKI Dysregulation of Calcium-Mediated Signaling TKIs and Sodium Channels: An Unexplored Territory TKIs and Heart Failure TKIs and Thromboembolism Monitoring and Treatment of TKI-Induced Cardiotoxicity Part III: Immune Checkpoint Inhibitors T-Cell Activation and Regulation Mechanisms of ICI-Mediated Cardiac Disorders Arrhythmias Myocarditis and Pericarditis Heart Failure Monitoring and Treatment of ICI-Associated Cardiotoxicity Part IV: CAR T-Cell Immunotherapy CAR T-Cell Mechanism of Action Proposed Mechanisms of Cardiotoxicity in CAR T-Cell Therapy JAK/STAT Signaling Pathway IL-6 TNFα Interleukin 1 Off-Target Affects Monitoring of CAR T-Cell Associated Cardiotoxicity Current and Proposed Treatments for CAR T-Cell-Induced Cardiotoxicity References Protein Phosphatase Signaling in Cardiac Myocytes Introduction The Kinase-Phosphatase Axis Protein Phosphatase Families and Genetics Localization and Binding Partners of Protein Phosphatases Mouse Models Protein Phosphatases in Cardiovascular Disease PP1 in Cardiovascular Disease PP2A in Cardiovascular Disease PP2B in Cardiovascular Disease Conclusions and Future Directions References Metabolic Regulation of Mitochondrial Dynamics and Cardiac Function Mitochondrial Dynamics: Fusion and Fission Events Diabetes-Related Cardiac Ischemia and Reperfusion Injury Diabetes-Related Cardiac Chronic Remodeling, Hypertrophy, and Failure Metabolic Control of Mitochondrial Dynamics: The Role of AMPK Concluding Remarks References NADPH Oxidase System Mediates Cholesterol Secoaldehyde-Induced Oxidative Stress and Cytotoxicity in H9c2 Cardiomyocytes Introduction Materials and Methods Chemicals, H9c2 Cardiomyocytes, and Cell Culture Supplies Synthesis of Cholesterol Secoaldehyde Cell Culture and Treatments Cell Proliferation and Metabolism Trypan Blue Exclusion Assay Measurement of Intracellular Peroxides Measurement of Hydrogen Peroxide Thiobarbituric Acid-Reactive Substances (TBARs) Measurement of Reduced Glutathione Levels Assay of Superoxide Dismutase Activity Measurement of Mitochondrial Transmembrane Potential Western Blot Analysis Statistical Analysis Results Apocynin Exacerbates While DPI Reduces the ChSeco-Induced Cytotoxic Response in H9c2 Cardiomyocytes NOS Inhibitors Attenuate the Formation of Peroxide or Peroxide-Like Substances in ChSeco-Exposed H9c2 Cardiomyocytes Apocynin Lowers the GSH Levels in ChSeco-Exposed Cardiomyocytes Apocynin But Not DPI Enhances the ChSeco-Induced Activation of SOD Activity in H9c2 Cardiomyocytes Apocynin and DPI Pretreatment in H9c2 Cardiomyocytes Reduces TBARs Formed in Response to the Exposure of ChSeco ChSeco-Induced Loss in Mitochondrial Transmembrane Potential Is Reversed by Pretreatments with Apocynin and DPI ChSeco-Induced Overexpression of pp38 and pSAPK in H9c2 Cardiomyocytes Is Mitigated by Pretreatments with Apo and DPI Discussion Conclusion References Lipid Mediators in Cardiovascular Physiology and Disease Introduction Lipid Mediators Oxylipins PUFA Reservoirs Oxylipin Synthesis Cyclooxygenase-Derived Oxylipins Lipoxygenase-Derived Oxylipins Cytochrome P450-Derived Oxylipins Conclusion and Future Perspectives References Cardiac Inflammasome and Arrhythmia Introduction Cardiac Electrophysiology Pathophysiology of AF Inflammasome Signaling Cardiac Inflammasome Signaling and Arrhythmogenesis Inflammasome-Mediated Pathogenesis of AF Nlrp3 Inflammasome Links AF Risk Factors to Atrial Arrhythmogenesis Nodal Signaling Points of Nlrp3 Activation Therapeutic Potential of Targeting the Cardiac NLRP3 Inflammasome Summary and Future Perspectives References Myocardial Fibrosis: Cell Signaling and In Vitro Modeling Introduction The Normal Myocardium Myocardial Fibrosis Modeling Myocardial Fibrosis Mechanotransduction Cell-Cell and Cell-ECM Interactions Pro-Fibrotic Soluble Mediators Conclusion References Neural Regulation of Cardiac Rhythm Introduction Neuronal Anatomy and Organization Cardiac Responses to Neurochemicals Adrenergic Signaling Muscarinic Signaling Co-transmission In vitro Models to Study Neural Regulation of Cardiac Rhythm Co-cultures Isolated Heart and Tissue Preparations Conclusions References Part II: Vascular Signaling Mechanisms of Lipoproteins and Reverse Cholesterol Transport in Atherosclerotic Cardiovascular Disease Introduction Lipoproteins Involved in Cholesterol Transport The Reverse Cholesterol Transport Pathway Mechanisms of Diseases Associated with Atherosclerotic CVD Genetic Predisposition to Cholesterol-Driven Cardiovascular Disease Therapeutic Approaches Targeting Lipoproteins LDL-C-Targeted Therapies HDL-C-Targeted Therapies References Atherosclerotic Plaque Regression: Future Perspective Introduction Development of Atherosclerotic Plaque and Formation of Primary Oxidation Products Role of Protein Carbonyls in Atherosclerotic Plaque Progression Factors Affecting Plaque Regression Increasing HDL Cholesterol Reverse Cholesterol Transport Plaque Regression: Current Approaches Increasing the Efflux of Cholesterol From Macrophages Increasing Transport of Cholesterol From Macrophages Through the Plasma to the Liver Increasing Uptake of Cholesterol by the Liver for Metabolism and Excretion Carbonyls Scavengers .Conclusion References Role of Bioactive Lipid, Phosphatidic Acid, in Hypercholesterolemia Drug-Induced Myotoxicity: Statin-Induced Phospholipase D (PLD) Lipid Signaling in Skeletal Muscle Cells Introduction Cardiovascular Disease Cholesterol and Cardiovascular Diseases Statins as the Endogenous Cholesterol-Lowering Drugs Lipid Signaling and Statin-Induced Myotoxicity or Myalgia Materials and Methods Materials In Vitro Cell Culture Assay of Phospholipase D (PLD) Activation Lactate Dehydrogenase (LDH) Release Assay of Cytotoxicity MTT Cell Proliferation Assay Cellular Morphology Cholesterol Determination Phospholipase D1 (PLD1) Phosphorylation Visualization by Confocal Immunofluorescence Microscopy Preparation of Solutions Containing Pharmacological Agents for Treatment of Cells Statistical Analysis Results Discussion References Cell-Cell Communication in the Vascular Endothelium Structural/Signaling Components Tight Junctions Gap Junctions Pannexin Channels Purinergic Signaling in Endothelial Cells Ca2+ Signaling Transmembrane Ca2+ Channels Intracellular Ca2+ Channels A Look Ahead Conclusion References Lysophosphatidic Acid Regulates Endothelial Barrier Integrity Introduction Vascular Endothelial Hyperpermeability in Diseases EC Cell–Cell Junctions Regulate EC Barrier Integrity Rho Family of GTPases Regulate EC Barrier Integrity LPA Production LPARs’ Expression in Endothelial Cells LPA in Endothelial Barrier Function in Lungs LPA in Endothelial Barrier Function in BBB LPA in Endothelial Barrier Function in Other Systems Molecular Mechanisms of LPA-Modulated Barrier Function Summary References Regulation of Vascular Endothelial Barrier Integrity and Function by Lipid-Derived Mediators Introduction Modulation of Endothelial Barrier Restoration by Barrier-enhancing Agents Prostaglandins and Leukotrienes in Endothelial Barrier Integrity Phospholipase D/Phosphatidic Acid Signaling and Endothelial Barrier Integrity Phosphatidic Acid Induces Endothelial Permeability Phospholipase D2 Facilitates Restoration of Endothelial Barrier Function In Vivo Central Role of VE-Cadherin Trafficking to Nascent Adherens Junctions (AJs) in Restoring Endothelial Barrier Integrity PLD2/PA Signaling Facilitates Endothelial Barrier Restoration by Enhancing VE-Cadherin Dephosphorylation Via Tyrosine-Protein Phosphatase Non-Receptor Type 14 (PTPN14) PLD2 Modulates Cortactin Phosphorylation in Formation of Lamellipodia, Resealing of AJ Barrier, and Restoration of Lung Vascular Barrier Integrity Lysophosphatidic Acid/LPARs in Endothelial Barrier Regulation Sphingolipids Modulate Endothelial Barrier Restoration and Integrity Ceramide in Endothelial Apoptosis and Permeability S1P Metabolism and Cell Function S1P and Endothelial Barrier Enhancement The S1P Analogs FTY720 and FTY-720 Phosphonate Modulate Endothelial Barrier Integrity SPHK1 as Potential Intracellular Target in Facilitating Endothelial Barrier Restoration S1P Lyase Targeting Promotes Endothelial Barrier Integrity S1P Transporter SPNS2 Regulates Lamellipodia Formation and Endothelial Barrier Function Mechanisms of S1P- and HGF-Mediated Endothelial Barrier Restoration Mechanisms of FTY720- and FTY720-Phosphonate-Mediated Endothelial Barrier Enhancement Oxidized Phospholipids and Endothelial Barrier Protection Conclusion and Perspective References Hyperglycemic Oxoaldehyde (Glyoxal)-Induced Vascular Endothelial Cell Damage Through Oxidative Stress Is Protected by Thiol Iron Chelator, Dimercaptosuccinic Acid – Role of Iron in Diabetic Vascular Endothelial Dysfunction Introduction Materials and Methods Materials Cell Culture Cell Treatment Cell Morphology Assay LDH Assay of Cytotoxicity MTT Assay of Cytotoxicity [3H]-Thymidine Incorporation Assay for Cell Proliferation Fluorescence Microscopy of Actin Stress Fibers Immunofluorescence Microscopy of ZO-1, Occludin, and AGEs Immunofluorescence Confocal Microscopy of Cortactin Measurement of Transendothelial Cell Electrical Resistance (TER) In Vitro Endothelial Cell Tube Formation Assay for Angiogenesis Reactive Oxygen Species (ROS) Determination by DCFDA Fluorescence Superoxide (O2−) Determination by DHE Fluorescence Reduced Glutathione (GSH) Determination FITC Paracellular Transport (Leak) Through the Endothelial Cell Monolayer Visualization of Free (Labile) Chelatable Iron in BPAECs by Fluorescence Microscopy Statistical Analysis Results Glyoxal Induces Cytotoxicity to BPAECs as Evidenced by LDH Release by Cells DMSA Protects Against Glyoxal-Induced LDH Release by BPAECs Glyoxal Inhibits MTT Reduction by BPAECs DMSA Protects Against Glyoxal-Induced Inhibition of MTT Reduction by BPAECs Glyoxal-Induced Cell Morphological Alterations Are Attenuated by DMSA in BPAECs DMSA Protects Against Glyoxal-Induced Inhibition of Cell Proliferation as Evidenced by Decrease in [3H]-Thymidine Incorporation in BPAECs DMSA Protects Against Glyoxal-Induced Inhibition of In Vitro Angiogenesis in BPAECs Glyoxal Induces ROS Formation in BPAECs Which Is Attenuated by DMSA Glyoxal Causes Thiol-Redox Alteration Through GSH Depletion Which Is Attenuated by DMSA in BPAECs DMSA Protects Against Glyoxal-Induced Loss of Transendothelial Electrical Resistance (TER) in BPAEC Monolayer DMSA Protects Against Glyoxal-Induced Paracellular Permeability (Leak) in BPAEC Monolayer DMSA Protects Glyoxal-Induced Cytoskeletal Rearrangement in BPAECs DMSA Protects Against Glyoxal-Mediated Formation of AGEs in BPAECs Iron (Fe2+) Exacerbates Glyoxal-Induced Cytotoxicity and ROS Formation in BPAECs Determination of Chelatable Iron (Fe) Availability in BLMVECs Discussion References Index