Front Cover

Endocrinology of the Heart in Health and Disease

Copyright Page

Contents

List of Contributors

Foreword

Preface

Acknowledgments

I. The Heart as an Endocrine Organ

1 Cardiac Natriuretic Peptides

Historical Perspective

Gene Structure of Natriuretic Peptides

Atrial Natriuretic Peptide

Brain or B-type Natriuretic Peptide

C-type Natriuretic Peptide

Translation, Processing, and Storage of Cardiac Natriuretic Peptides

Atrial Natriuretic Peptide

Brain or B-Type Natriuretic Peptide

C-Type Natriuretic Peptide

Circulating Concentrations, Forms, and Metabolism of Natriuretic Peptides

Circulating Levels

Circulating Forms and Metabolism

Natriuretic Peptide Receptors

Circulating Natriuretic Peptide Signal Peptides

Assays Measuring Natriuretic Peptides in the Circulation

Bioactivity

Hemodynamic

Renal

Endocrine

Integrative Role in Physiology and Pathophysiology

Natriuretic Peptide as Therapeutic Agents

Enhancing Bioactivity

NEP-I

Combined ACE and NEP Inhibitors

Combined ARB and NEP Inhibitors—New Frontier in Heart Failure Therapy

Natriuretic Peptides as Biomarkers in Heart Failure

Natriuretic Peptides in Diagnosis of Acute Decompensated Heart Failure

BNP and NT-proBNP for Community Screening for Cardiac Impairment

B-Type Natriuretic Peptides for Prognosis in Heart Failure

Marker Guided Therapy in Heart Failure

References

2 Adrenomedullin

Introduction

Molecular Forms, Structure, and Structure-Activity Relationships of Adrenomedullin

The Adrenomedullin Receptor

Cardiac Actions of Adrenomedullin

Effect of Adrenomedullin on Cardiac Contractility

Effect of Adrenomedullin on Cardiac Structure

Pathophysiological Function of Adrenomedullin in Cardiac Disease

Cardiac Hypertrophy and Heart Failure

Acute Myocardial Infarction

Ischemia/Reperfusion

Clinical Applications of Adrenomedullin to Cardiac Disease

Effect of Adrenomedullin Administration in Patients with Heart Failure

Clinical Application of Adrenomedullin in Acute Myocardial Infarction

Clinical Trials with Adrenomedullin

Conclusion

References

3 Endothelin-1 as a Cardiac-Derived Autocrine, Paracrine and Intracrine Factor in Heart Health and Disease

Introduction

Cardiac Production of ET-1

Cardiac ET-1 Production in Heart Disease

Expression of Cardiac ET Receptors

Intracellular ET Receptors: Evidence for an Intracrine Role of ET-1 in the Cardiac Cell

Cardiac Effects of ET-1

Mechanisms Underlying Inotropic Responses

Physiological and Pathophysiological Roles of Cardiac-Derived ET-1: General Concepts

ET-1 and the Aging Heart

Association of ET-1 With Cardiac Diseases

ET-1 in Cardiac Hypertrophy and Heart Failure

Endogenous Modulation of ET-1: Keeping ET-1 in Check?

Potential Beneficial Effects of ET-1 in Cardiac Function

Development of Clinical Strategies aimed at Targeting ET-1

Clinical Evaluation of ET Receptor Antagonists for Treating Heart Disease

Potential Reasons for Failed Clinical Trials

Concluding Comments

Acknowledgements

References

4 The Cardiokines: An Expanding Family of the Heart Secretome

Introduction

Cellular Components of the Heart Involved in the Cardiac Secretome

Myofibroblasts, Myocytes and Vascular Cells

Cardiac Conduction Cells

Cardiac Adipocytes

Resident Immune Cells

Extracellular Matrix

The Autocrine, Paracrine, and Endocrine Heart: Components of the Cardiac Secretome

Growth Factor Generation in the Heart

Transforming Growth Factor-Beta

Vascular Endothelial Cell Growth Factor

Fibroblast Growth Factor-2 and FGF-16

Inflammatory Mediators Generated in the Heart

The Inflammasome

IL-1α, IL-1β, IL-18, and IL-33

Interleukin-6

Tumor Necrosis Factor (TNF-α) and Soluble CD40 Ligand (sCD40L)

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF), Secreted Frizzled Related Protein (SFRP)-2, and Protease Inhibi ...

High Mobility Group box 1 Protein

Macrophage Migration Inhibitory Factor

Cardiac Exosomes and miRNA

Insight into Future Directions

Acknowledgement

References

5 Novel Small Peptide Hormones

Introduction

Endocrine Factors Regulating Blood Pressure and Cardiac Function: Neuronostatin and Adropin

Neuronostatin: Discovery and Sites of Production

Neuronostatin and the Central Control of Blood Pressure

Neuronostatin and Cardiac Function

Assessing the Physiologic Relevance of Neuronostatin

Adropin: A Cardio-Metabolic Peptide

Adropin: An Independent Risk Factor for Cardiovascular Disease

Novel Adipokines in the Control of Cardiovascular Function: Nesfatin-1 and Omentin

Adipose Tissue as an Endocrine Organ

Nesfatin-1: Discovery, Production, and Signaling

Nesfatin-1 and the Central Control of Blood Pressure

Nesfatin-1 and Cardiac Function

Omentin: Discovery, Expression, and Signaling

Omentin and the Vasculature

The Protective Effect of Omentin in the Heart

Role of Myokines in Cardiovascular Health: Irisin

Skeletal Muscle as an Endocrine Organ

Irisin, a Novel Myokine

Irisin and Maintenance of the Vascular Endothelium

Modulatory Peptides Encoded by Upstream Short Open Reading Frames of Hormone Receptors: PEP7

Summary and Conclusions

References

II. The Heart as an Endocrine Target

6 Gut-Derived Hormones—Cardiac Effects of Ghrelin and Glucagon-Like Peptide-1

Ghrelin

Gene Structure and Derived-Peptides

Ghrelin Receptors

Type 1a GHS Receptor (GHS-R1a)

Non type 1a GHS Receptors

Ghrelin Effects on the Cardiovascular System

Vasoactive Function

Modulation of the Sympathetic Control of Cardiovascular Function

Inotropic Regulation

Antiinflammatory Action

Antiapoptotic Effects in Cardiac Cells

Ghrelin in the Pathophysiology of Chronic Heart Failure

Ghrelin in the Pathophysiology of Myocardial Infarction

Glucagon-Like Peptide-1

Gene Structure and Derived-Peptides

GLP-1 Receptor

GLP-1 Receptor Agonists (GLP-1 RAs)

DPP-4 Inhibitors (Gliptins)

Cardiovascular Effects of GLP-1

Diabetic Cardiomyopathy

Myocardial Infarction

Chronic Heart Failure

References

7 Fat Hormones, Adipokines

Introduction

Obesity as a Chronic Proinflammatory State

Proinflammatory Adipokines

Leptin

Resistin

Visfatin

Adipocyte–Fatty Acid Binding Protein

Anti-inflammatory Adipokines

Adiponectin

Omentin

Chemerin

Vaspin

Conclusion

References

8 Neuronal Hormones and the Sympathetic/Parasympathetic Regulation of the Heart

Introduction

Electrical System of the Heart

Sympathetic Nervous System of the Heart

Parasympathetic Nervous System of the Heart

Measuring Autonomic Nervous System Regulation of the Heart

Circadian Rhythm Regulation of the Autonomic System

Other Endocrine Organs and the Heart: Posterior Pituitary

Miscellaneous Hormones and the Heart

Physiology and Pathophysiology of Cardiovascular Function Involving the Autonomic System: Pregnancy and the Baroreflex

Diabetic Autonomic Dysfunction/Metabolic Syndrome (A Sympathetic Disease?) and its Effects on the Heart

Postural Tachycardia

Effect of Sleep Deprivation on Cardiovascular Regulation

Concluding Remarks

References

9 Renin Angiotensin Aldosterone System and Heart Function

The Conventional Renin Angiotensin Aldosterone System

RAAS and Heart Cell Communication

AT1 Receptor as a Mechanosensor

Role of ACE Inhibitors and AT1 Receptor Blockers

ACE2/Ang (1-7) /Mas Receptor Axis Activation

Local Cardiac RAAS, the Intracrine Component

Intracellular Renin Alters Chemical Communication and Metabolic Cooperation

Mitochondria, the Nucleus and the Intracrine Renin-Angiotensin System

Aldosterone and Mineralocorticoid Receptor

New Developments

Angiotensin (1-12)

Neprilysin Inhibitors

(Pro)renin Receptor

Renin Inhibition

References

10 Nuclear Receptors and the Adaptive Response of the Heart

Nuclear Receptors: Introduction

PGC Coactivators in the Developing and Diseased Heart

Estrogen Receptors

Structure and Function

Estrogen Cell Signaling

Calcium Handling

Regulation of Mitochondrial Mass, Ca2+, and Apoptosis

Ischemic Heart Disease

Estrogen-Related Receptors

Structure and Function

Fatty Acid Oxidation

Transcriptional Control of Metabolism

Pathology

Glucocorticoid Receptors

Structure and Function

Genomic and Nongenomic Signaling

Cardiomyocyte Ca2+ Handling and Contractile Function

Pathology

Mineralocorticoid Receptors

Structure and Function

Genomic and Nongenomic Signaling

Pathophysiology: Inflammation and Fibrosis

Mineralocorticoid Antagonists in Treating Heart Failure

Thyroid Hormone Receptors

Mechanisms of Thyroid Hormone Action

Pathophysiology

THR Mutations

TH and THR Nonnuclear Regulation

PPAR Family Receptors

Domain Structure

Physiological Functions

PPAR Ligands

Posttranslational Mechanisms of PPAR Regulation

Emerging and Associated Players

Vitamin D Receptors

Summary

References

11 Adrenergic Receptors

Adrenergic Signaling: Systematic and Updated Overview

Sympathetic System and Hypertension

Role of Adrenergic System in Regulation of vascular Homeostasis and Oxidative Stress

Adrenergic Signaling and ROS

The Role of G Protein–Coupled Receptor Kinase 2 in Vascular Homeostasis

Adrenergic Signaling in Heart Failure

Adrenergic System in the Heart: Beyond the Regulation of Contractility

Adrenergic Receptors and Cardiac Metabolism

Role of Adrenergic Receptors in the Pathophysiology of Cardiac Hypertrophy

GRK2 Subcellular Localization: A Molecular Link Between Myocardial Contractility and Cardiac Metabolism

Pharmacology of Adrenergic Receptor Blockade

α-Adrenergic Receptor Blockade

β-Adrenergic Receptor Blockade

References

12 Insulin Signaling in Cardiac Health and Disease

Abbreviations

Introduction

Functional Importance of Insulin Receptor Signaling in the Heart

Metabolic Effects of Insulin Signaling in the Myocardium

Effects of Insulin on Glucose Transport

Effects of Insulin on Glucose Utilization

Effects of Insulin on Fatty Acid Utilization

Effects of Insulin on Protein Synthesis

Cardiac Insulin Signaling During Obesity and Type 2 Diabetes

Insulin Signaling and Cardiac Hypertrophy

Cardio-Protective Role of Insulin Signaling in Ischemia Reperfusion and Contractile Failure

Scope and Future Perspectives

References

Index

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