![conference banner](/images/conference-banner.jpeg)
Abstract
Background: Excessive norepinephrine (NE) release in the ischemic heart elicits severe and often lethal arrhythmias. Resident cardiac mast cells synthesize and store active renin, which is released upon degranulation, causing the activation of a local cardiac renin-angiotensin system (RAS) responsible for NE release and consequent arrhythmias. Toxic aldehydes, known to be formed by lipid peroxidation in ischemia/reperfusion (I/R), have been shown to degranulate mast cells and activate a local RAS.
Objective: To provide an up-to-date description of the roles of ischemic preconditioning (IPC) and Gicoupled receptors in anti-RAS cardioprotection.
Methods: Ex-vivo I/R models in cavian and murine hearts, and human and murine mast cell lines in vitro.
Results: IPC not only drastically reduces the injury subsequent to a prolonged ischemic event, but also decreases mast cell renin release, thus affording anti-RAS cardioprotection. Similarly, activation of Gicoupled receptors, such as histamine-H4, adenosine-A3 and sphingosine-1-phosphate-S1P1 receptors, all expressed at the mast cell surface, mimic the cardioprotective anti-RAS effects of IPC. The mechanism of this action depends on the sequential activation of a specific isoform of protein kinase C, PKCε, and mitochondrial aldehyde dehydrogenase-type 2 (ALDH2). Increased ALDH2 enzymatic activity exerts a pivotal role in the sequential inhibition of aldehyde-induced mast-cell renin release, prevention of RAS activation, reduction of NE release and alleviation of reperfusion arrhythmias.
Conclusion: These recently discovered protective pathways indicate that activation of mast-cell Gicoupled receptors and subsequent ALDH2 phosphorylation/activation represent a novel therapeutic target for the alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.
Keywords: Aldehyde Dehydrogenase type 2, Gi-coupled proteins, Ischemia/Reperfusion, Ischemic Preconditioning, Mast cells, Norepinephrine.
Current Medicinal Chemistry
Title:Salvaging the Ischemic Heart: Gi-Coupled Receptors in Mast Cells Activate a PKCε/ALDH2 Pathway Providing Anti-RAS Cardioprotection
Volume: 25 Issue: 34
Author(s): Alice Marino and Roberto Levi*
Affiliation:
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065,United States
Keywords: Aldehyde Dehydrogenase type 2, Gi-coupled proteins, Ischemia/Reperfusion, Ischemic Preconditioning, Mast cells, Norepinephrine.
Abstract: Background: Excessive norepinephrine (NE) release in the ischemic heart elicits severe and often lethal arrhythmias. Resident cardiac mast cells synthesize and store active renin, which is released upon degranulation, causing the activation of a local cardiac renin-angiotensin system (RAS) responsible for NE release and consequent arrhythmias. Toxic aldehydes, known to be formed by lipid peroxidation in ischemia/reperfusion (I/R), have been shown to degranulate mast cells and activate a local RAS.
Objective: To provide an up-to-date description of the roles of ischemic preconditioning (IPC) and Gicoupled receptors in anti-RAS cardioprotection.
Methods: Ex-vivo I/R models in cavian and murine hearts, and human and murine mast cell lines in vitro.
Results: IPC not only drastically reduces the injury subsequent to a prolonged ischemic event, but also decreases mast cell renin release, thus affording anti-RAS cardioprotection. Similarly, activation of Gicoupled receptors, such as histamine-H4, adenosine-A3 and sphingosine-1-phosphate-S1P1 receptors, all expressed at the mast cell surface, mimic the cardioprotective anti-RAS effects of IPC. The mechanism of this action depends on the sequential activation of a specific isoform of protein kinase C, PKCε, and mitochondrial aldehyde dehydrogenase-type 2 (ALDH2). Increased ALDH2 enzymatic activity exerts a pivotal role in the sequential inhibition of aldehyde-induced mast-cell renin release, prevention of RAS activation, reduction of NE release and alleviation of reperfusion arrhythmias.
Conclusion: These recently discovered protective pathways indicate that activation of mast-cell Gicoupled receptors and subsequent ALDH2 phosphorylation/activation represent a novel therapeutic target for the alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.
Export Options
About this article
Cite this article as:
Marino Alice and Levi Roberto*, Salvaging the Ischemic Heart: Gi-Coupled Receptors in Mast Cells Activate a PKCε/ALDH2 Pathway Providing Anti-RAS Cardioprotection, Current Medicinal Chemistry 2018; 25 (34) . https://dx.doi.org/10.2174/0929867325666180214115127
DOI https://dx.doi.org/10.2174/0929867325666180214115127 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the Treatment of Chronic Inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
![Wayfinder Image](/images/wayfinder.jpg)
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Usefulness of Magnetic Resonance Imaging in Cardiac and Enovascular Intervention
Current Medical Imaging Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?
Anti-Cancer Agents in Medicinal Chemistry Effects of Oral L-Citrulline Supplementation on Lipoprotein Oxidation and Endothelial Dysfunction in Humans with Vasospastic Angina
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Novel Insights into the Pervasive Role of M3 Muscarinic Receptor in Cardiac Diseases
Current Drug Targets Pulmonary Arterial Hypertension in Connective Tissue Diseases
Current Respiratory Medicine Reviews Dietary Fiber Gap and Host Gut Microbiota
Protein & Peptide Letters The Prevalence of Shiga Toxin-1 in Non-<i>Shigella</i> Dysenteriae Isolates Collected from Diarrhea Samples in Patients, Ahvaz, Iran
Infectious Disorders - Drug Targets Sleep Disorders Research From 1945 to 2020: A Bibliometric Analysis
CNS & Neurological Disorders - Drug Targets Statins in Peripheral Arterial Disease
Current Pharmaceutical Design Nanoantioxidant/Antioxidant Therapy in 2019-nCoV: A New Approach to Reactive Oxygen Species Mechanisms
Current Drug Therapy Oxidative Stress Modulation Through Habitual Physical Activity
Current Pharmaceutical Design Impact of Hydration on Exercise Performance and Physiological Responses
Current Nutrition & Food Science Development and Potential Utility of Dual and Triple NK Receptor Antagonists
Current Topics in Medicinal Chemistry Effect of Aging On Angiogenesis and Arteriogenesis
Current Cardiology Reviews An update on the Management and Treatment of Deep Vein Thrombosis
Cardiovascular & Hematological Agents in Medicinal Chemistry Role of Ca2+-Sensitive K+ Currents in Controlling Ventricular Repolarization: Possible Implications for Future Antiarrhytmic Drug Therapy
Current Medicinal Chemistry Endoplasmic Reticulum Stress as a Novel Therapeutic Target in Heart Diseases
Cardiovascular & Hematological Disorders-Drug Targets Cytochrome P450 1B1 and 2C9 Genotypes and Risk of Ischemic Vascular Disease, Cancer, and Chronic Obstructive Pulmonary Disease
Current Vascular Pharmacology The Role of Vitamin D in Dyslipidemia and Cardiovascular Disease
Current Pharmaceutical Design Exploration of Epigenetic State Hyperdopaminergia (Surfeit) and Genetic Trait Hypodopaminergia (Deficit) during Adolescent Brain Development
Current Psychopharmacology