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The Protective Arm of the Renin Angiotensin System (RAS)

Functional Aspects and Therapeutic Implications

1st Edition - April 18, 2015

Editors: Thomas Unger, U. Muscha Steckelings, Robson Augusto Souza dos Santos

Paperback ISBN:

9 7 8 - 0 - 1 2 - 8 0 1 3 6 4 - 9

eBook ISBN:

9 7 8 - 0 - 1 2 - 8 0 1 4 8 5 - 1

The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a… Read more

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The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a distinct part of the renin–angiotensin system (RAS), providing readers with early insight into a complex system which will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1–7) peptide with its receptor Mas, and the enzyme ACE 2, which exert significant beneficial, health-promoting actions by counterbalancing the well-known harmful arm of the RAS with its classical angiotensin AT1 receptor. This innovative concept of the protective arm of the RAS, examined in this reference, represents an indispensable background and will be a strong support for biomedical students, researchers, cardiologists, surgeons, nephrologists, diabetologists, and endocrinologists, as well as any other physician or researcher concerned with RAS physiology, pathophysiology and clinical implications.

Chapter 1: The Angiotensin AT₂ Receptor: From Enigma to Therapeutic Target
- Abstract
- Introduction
Chapter 2: The AT₂ Receptor: Historical Perspective
- Abstract
- Background to the Early Involvement of Ciba-Geigy in the Angiotensin Field
- Two Ang II Receptor Subtypes
- Angiotensin II Receptor Nomenclature
- Early Research on the Role of the AT₂ Receptor
- Conclusion
Chapter 3: Animal Models with a Genetic Alteration of AT₂ Expression
- Abstract
- Introduction
- Blood Pressure
- Cardiac Disease
- Vascular Disease
- Renal Disease
- Neural Disease
- Conclusion
Chapter 4: AT₂ Receptor Signaling: Solved and Unsolved
- Abstract
- Introduction
- AT₂R Dimerization
- Proliferation and Differentiation
- Apoptosis
- Inflammation
- Fibrosis
- Solved and Unsolved Issues
Chapter 5: AT₁R–AT₂R Cross Talk
- Abstract
- Cross Regulation of Angiotensin II Type 1 Receptor and the Angiotensin II Type 2 Receptor
- Functional Significance of the AT₁R–AT₂R Cross Talk
- Conclusion
Chapter 6: The Angiotensin AT₂ Receptor in Myocardial Infarction
- Abstract
- Introduction
- AT₂ Receptor Expression in the Heart
- Acute-Phase Postmyocardial Infarction
- Late-Phase Postmyocardial Infarction
- Conclusion
Chapter 7: AT₂R, Vascular Effects, and Blood Pressure
- Abstract
- Acknowledgments
- Introduction
- AT₂ Vasorelaxation: In Vitro Preclinical Studies
- Acute AT₂R Vasodilatation/BP Effects: In Vivo Preclinical Studies
- Chronic AT₂R Effects on BP: Preclinical Studies
- Human Vascular AT₂R Function: ex vivo and In Vivo Studies
- AT₂R Vasorelaxation: Why Is There no Translation into Antihypertensive Effects in Chronic Studies?
Chapter 8: AT₂R in Nervous System
- Abstract
- Introduction
- AT₂R Expression in CNS
- AT₂R Expression in Neuronal Injury
- AT₂R-Mediated Effects in CNS Cells
- AT₂R in Peripheral Neuronal Injury
- AT₂R Stimulation in Stroke
- AT₂R in Spinal Cord Injury
- AT₂R in Multiple Sclerosis
- AT₂R in Traumatic Brain Injury
- Conclusion
Chapter 9: Roles of AT₂R in Cognitive Function
- Abstract
- Acknowledgments
- Introduction
- Preventive Effects of ARB on Cognitive Decline and Dementia
- Protection Against Ischemic Brain Damage by AT₂R Stimulation
- Role of AT₂R Stimulation in Cognitive Function
- Role of AT₂R-Associated Proteins in Cognitive Function
- Conclusion
Chapter 10: The Protective Role of Angiotensin II (AT₂) Receptors in Renal Disease: Molecular Mechanisms and Indications for AT₂ Agonist Therapy
- Abstract
- Introduction
- Renal AT₂R Expression
- Findings from AT₂R Knockout (AT₂KO) Mice
- AT₂R-Mediated Signaling Pathways
- Renoprotective Mechanisms of AT₂R Stimulation
- AT₂R in Renal Disease Associated with Obesity/Diabetes
- Conclusion
Chapter 11: AT₂ Receptors and Natriuresis
- Abstract
- Introduction
- Renal Expression of AT₂Rs
- AT₂R Induction of Natriuresis: Initial Evidence
- Role of Angiotensin III in AT₂R-Induced Natriuresis
- Nephron Sites and Mechanisms of AT₂R-Induced Natriuresis via ANG III
- AT₂R-Dopamine D₁-Like Receptor Interactions
- Physiological Significance of Renal AT₂Rs in Renal Na⁺ Excretion
- AT₂R-Induced Natriuresis in Disease States
- AT₂R Agonist Administration and Natriuresis
- Conclusion
Chapter 12: The Role of the AT₂R in Vascular Remodeling
- Abstract
- Introduction
- The Theoretical Concept of the Role of AT₂R in Vascular Remodeling
- AT₂R and Hypertension-Induced Vascular Remodeling
- AT₂R and Atherosclerosis
- AT₂R and Aortic Aneurysm
- Conclusion
Chapter 13: The AT₂ Receptor and Inflammation
- Abstract
- Introduction
- AT₂R Signaling in Inflammation
- Inflammation in Cardiovascular Disease and the Role of the AT₂ Receptor
- Inflammation in Autoimmune Disease and the Role of the AT₂ Receptor
- Conclusions
Chapter 14: The AT₂ Receptor and Interacting Proteins (ATIPs) in Cancer
- Abstract
- Acknowledgments
- The Renin–Angiotensin System and Cancer
- The AT₂ Receptor and Cancer
- AT₂ Receptor-Interacting Proteins (ATIPs) and Cancer
Chapter 15: AT₂R and Sympathetic Outflow
- Abstract
- Acknowledgments
- Introduction
- AT₂R Ontogeny in Rodent Brain
- Effect of AT₂R Activation on Neuronal Electrophysiological Characteristics
- AT₂R and Sympathetic Regulation in Normal States
- Effects of the AT₂R on Sympathetic Outflow in Pathological Conditions and Therapeutic Potential
- Conclusion and Perspectives
Chapter 16: Metabolic Effects of AT₂R Stimulation in Adipose Tissue
- Abstract
- Introduction
- Metabolic Function of AT₂R: The Lessons from ARBs
- Metabolic Function of AT₂R: The Lessons from AT₂R-Deficient Mice
- Metabolic Function of AT₂R: Experiments with Direct AT₂R Stimulation
Chapter 17: Sex Differences in AT₂R Expression and Action
- Abstract
- Basis for Sex Differences in Function
- Regulation of Arterial Pressure and Renal Function
- Evidence for a Differential Role for the AT₂R in Other Disease Conditions
- Reproduction
- Conclusion
Chapter 18: Discovery of Nonpeptide, Selective AT₂ Receptor Agonists
- Abstract
- Acknowledgments
- Selective Drug-like AT₂R Agonists from Nonpeptide, Nonselective AT₁/AT₂ Receptor Ligands
- Selective Drug-like AT₂R Agonists from the Nonselective Parent Peptide Ang II
- Conversion of AT₂R Agonists to AT₂R Antagonists
Chapter 19: Angiotensin-Based Peptides as AT₂R Agonists
- Abstract
- Acknowledgments
- Introduction
- Endogenous Angiotensin Peptides
- Synthetic Peptides
- Conclusions
Chapter 20: Potential Clinical Application of Angiotensin 2 Receptor Agonists
- Abstract
- Introduction
- Preclinical Testing
- Investigational New Drug Application
- Clinical Trials
- Potential Therapeutic Indications for AT₂R Agonists
- Conclusion
Chapter 21: Angiotensin-(1-7) and Mas: A Brief History
- Abstract
- Introduction
- Discovery of Mas: Is It a Proto-Oncogene?
- Functions of Mas: Is It an Ang II Receptor?
- Mas, Its Antisense RNA, and Imprinting
- Mas Expression
- Mas Functions: Mas-Deficient Mice
- Discovery of Ang-(1-7)
- Closing the Gap: Mas Is an Ang-(1-7) Receptor
Chapter 22: Animal Models with a Genetic Alteration of the ACE2/Ang-(1-7)/Mas Axis
- Abstract
- Introduction
- Transgenic Animal Technology: A Brief Update
- Transgenic and KO Rodent Models of the ACE2/Ang-(1-7)/Mas Axis
- Conclusions and Outlook
Chapter 23: Mas Signaling: Resolved and Unresolved Issues
- Abstract
- Acknowledgments
- Introduction
- Expression of Mas
- Mas as a GPCR
- Early Discovery of Mas and Its Signaling Pathways
- Identifying Ang-(1-7) Targets Through Proteomics
- Ang-(1-7)/Mas Signaling Through Akt
- Ang-(1-7)/Mas Signaling and Nitric Oxide Production
- Mas and MAPK Signaling
- Mas and RhoA
- Biological Significance of Mas Signaling: Insights from Mas-Knockout Mice
- Unresolved Issues
- Conclusions
Chapter 24: Mas/AT₂ Cross Talk
- Abstract
Chapter 25: ACE2 Cell Biology, Regulation, and Physiological Functions
- Abstract
- Introduction
- ACE2: Discovery and Basic Biology
- ACE2 Regulation
Chapter 26: Mas in Myocardial Infarction and Congestive Heart Failure
- Abstract
- Myocardial Infarction and Congestive Heart Failure
- Renin–Angiotensin System and Cardiac Remodeling
- Inflammatory Phase
- Proliferative Phase
- Maturation Phase
Chapter 27: Mas Receptor: Vascular and Blood Pressure Effects
- Abstract
Chapter 28: Mas and Neuroprotection in Stroke
- Abstract
- Introduction
- Neuroprotection and the RAS
- Mechanisms of Protection
- Translation
- Conclusion
Chapter 29: Mas in the Kidney
- Abstract
- Introduction
- Role of ACE2/Ang-(1-7)/Mas in Renal Physiology
- Physiopathological Role of ACE2/Ang-(1-7)/Mas in Renal Diseases
- Concluding Remarks
Chapter 30: Mas and Inflammation
- Abstract
- Introduction
- ACE2/Ang-(1-7)/Mas Axis in Cytokine Regulation and Cellular Recruitment
- ACE2/Ang-(1-7)/Mas Axis and Fibrogenic Pathways
- Concluding Remarks
Chapter 31: ACE2 and Glycemic Control
- Abstract
- ACE2/ANG-(1-7)/MAS: Role in Glycemic Control
- ADAM17: A Potential Mechanism for ACE2 Shedding?
- Perspective
Chapter 32: Angiotensin-(1-7) and Cancer
- Abstract
- Historical Perspective
- Ang-(1-7) in Lung Cancer: Role in Proliferation and Angiogenesis
- Ang-(1-7) in Breast Cancer: Role in Tumor Fibrosis
- Ang-(1-7) in Prostate Cancer: Role in Regulation of Angiogenic Factors and Metastasis
- Ang-(1-7) and Clinical Trials
- Conclusion
Chapter 33: Mas and the Central Nervous System
- Abstract
- Mas Receptor Distribution in the Brain
- Mas Receptor-Triggered Actions in the Central Nervous System
- Mas Receptor and Central Neurotransmitters
- Concluding Remarks
Chapter 34: Role of the Alternate RAS in Liver Disease and the GI Tract
- Abstract
- Introduction
- The Classic RAS and Liver Fibrosis
- ACE Inhibitors and AT₁R Blockers in the Treatment of Liver Fibrosis
- The Alternate RAS and Liver Fibrosis
- Role of the RAS in Hepatic Resistance and Portal Hypertension
- Role of the Alternate RAS in the Gut
- Conclusion
Chapter 35: Metabolic Role of Angiotensin-(1-7)/Mas Axis
- Abstract
- Introduction
- Ang-(1-7)/Mas Modulating Insulin Effects and Signaling
- Liver Metabolic Effects of Ang-(1-7)/Mas Axis
- New Metabolic Remarks and Perspectives
Chapter 36: Mas and the Reproductive System
- Abstract
- Introduction
- Mas and the Female Reproductive System
- Mas and the Male Reproductive System
- Summary and Perspectives
Chapter 37: ACE2/Ang-(1-7)/Mas Axis and Physical Exercise
- Abstract
- Protective Effects of Physical Exercise
Chapter 38: Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Axis: Emerging Pharmacological Target for Pulmonary Diseases
- Abstract
- Introduction
- Evidence for the Existence of Vasodeleterious and Vasoprotective Axes of the RAS in the Lungs
- The ACE2/Ang-(1-7)/Mas Axis in Pulmonary Diseases
- The ACE2/Ang-(1-7)/Mas Axis Protects Against ARDS and PAH
- The ACE2/Ang-(1-7)/MAS Axis in PF
- Therapeutic Strategies to Activate the ACE2/Ang-(1-7)/Mas Axis
- ACE2 Activators
- Strategies Targeting Ang-(1-7)
- Mas Receptor Agonists
- Future Perspectives
- Conclusions
Chapter 39: Nanocarriers for Improved Delivery of Angiotensin-(1-7)
- Abstract
- Introduction
- Liposome Formulations of Ang-(1-7)
- Cyclodextrin-Based Oral Formulation of Ang-(1-7)
- Conclusion
Chapter 40: Mas Agonists
- Abstract
- Introduction
- Mas Agonists
- Conclusions
Chapter 41: Preclinical and Clinical Development of Angiotensin Peptides (Mas/Ang(1-7)/ACE-2): Future Clinical Application
- Abstract
- Introduction
- The Renin–Angiotensin System in Bone Marrow and Hematopoiesis
- Clinical Development of A(1-7) for Hematopoietic Indications
- Conclusions
Index