Cardiovascular Signaling in Health and Disease

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