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Kaplan A, El‐Samadi L, Zahreddine R, Amin G, Booz GW, Zouein FA. Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure. Acta Physiol (Oxf) 2025; 241:e70010. [PMID: 39960030 PMCID: PMC11831727 DOI: 10.1111/apha.70010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 01/12/2025] [Accepted: 01/20/2025] [Indexed: 02/20/2025]
Abstract
G protein-coupled receptor kinase 2 (GRK2) with its multidomain structure performs various crucial cellular functions under both normal and pathological conditions. Overexpression of GRK2 is linked to cardiovascular diseases, and its inhibition or deletion has been shown to be protective. The functions of GRK2 extend beyond G protein-coupled receptor (GPCR) signaling, influencing non-GPCR substrates as well. Increased GRK2 in heart failure (HF) initially may be protective but ultimately leads to maladaptive effects such as GPCR desensitization, insulin resistance, and apoptosis. The multifunctional nature of GRK2, including its action in hypertrophic gene expression, insulin signaling, and cardiac fibrosis, highlights its complex role in HF pathogenesis. Additionally, GRK2 is involved in mitochondrial biogenesis and lipid metabolism. GRK2 also regulates epinephrine secretion from the adrenal gland and its increase in circulating lymphocytes can be used to monitor HF status. Overall, GRK2 is a multifaceted protein with significant implications for HF and the regulation of GRK2 is crucial for understanding and treating cardiovascular diseases.
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Affiliation(s)
- Abdullah Kaplan
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Cardiology ClinicKemer Public HospitalAntalyaTurkey
| | - Lana El‐Samadi
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
| | - Rana Zahreddine
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
| | - Ghadir Amin
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - George W. Booz
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - Fouad A. Zouein
- Department of Pharmacology and ToxicologyAmerican University of Beirut Faculty of MedicineBeirutLebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of ExcellenceAmerican University of Beirut Medical CenterBeirutLebanon
- Department of Pharmacology and Toxicology, School of MedicineUniversity of Mississippi Medical CenterJacksonMississippiUSA
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Dong ZK, Wang YF, Li WP, Jin WL. Neurobiology of cancer: Adrenergic signaling and drug repurposing. Pharmacol Ther 2024; 264:108750. [PMID: 39527999 DOI: 10.1016/j.pharmthera.2024.108750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/04/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Cancer neuroscience, as an emerging converging discipline, provides us with new perspectives on the interactions between the nervous system and cancer progression. As the sympathetic nervous system, in particular adrenergic signaling, plays an important role in the regulation of tumor activity at every hierarchical level of life, from the tumor cell to the tumor microenvironment, and to the tumor macroenvironment, it is highly desirable to dissect its effects. Considering the far-reaching implications of drug repurposing for antitumor drug development, such a large number of adrenergic receptor antagonists on the market has great potential as one of the means of antitumor therapy, either as primary or adjuvant therapy. Therefore, this review aims to summarize the impact of adrenergic signaling on cancer development and to assess the status and prospects of intervening in adrenergic signaling as a therapeutic tool against tumors.
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Affiliation(s)
- Zi-Kai Dong
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China; Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China
| | - Yong-Fei Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China; Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China
| | - Wei-Ping Li
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China; Department of Urology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Wei-Lin Jin
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China; Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China.
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3
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Underwood L, Jiang CS, Oh JY, Sato PY. Unheralded Adrenergic Receptor Signaling in Cellular Oxidative Stress and Death. CURRENT OPINION IN PHYSIOLOGY 2024; 40:100766. [PMID: 39070968 PMCID: PMC11271747 DOI: 10.1016/j.cophys.2024.100766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Catecholamines (CAs) bind and activate adrenergic receptors (ARs), thus exuding a key role in cardiac adaptations to global physiological queues. Prolonged exposure to high levels of CAs promotes deleterious effects on the cardiovascular system, leading to organ dysfunction and heart failure (HF). In addition to the prominent role of ARs in inotropic and chronotropic responses, recent studies have delved into elucidating mechanisms contributing to CA toxicity and cell death. Central to this process is understanding the involvement of α1AR and βAR in cardiac remodeling and mechanisms of cellular survival. Here, we highlight the complexity of AR signaling and the fundamental need for a better understanding of its contribution to oxidative stress and cell death. This crucial informational nexus remains a barrier to the development of new therapeutic strategies for cardiovascular diseases.
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Affiliation(s)
- Lilly Underwood
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
| | - Chun-Sun Jiang
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
| | - Joo-Yeun Oh
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
| | - Priscila Y Sato
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
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Li Y, Li B, Chen WD, Wang YD. Role of G-protein coupled receptors in cardiovascular diseases. Front Cardiovasc Med 2023; 10:1130312. [PMID: 37342437 PMCID: PMC10277692 DOI: 10.3389/fcvm.2023.1130312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/09/2023] [Indexed: 06/22/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death globally, with CVDs accounting for nearly 30% of deaths worldwide each year. G-protein-coupled receptors (GPCRs) are the most prominent family of receptors on the cell surface, and play an essential regulating cellular physiology and pathology. Some GPCR antagonists, such as β-blockers, are standard therapy for the treatment of CVDs. In addition, nearly one-third of the drugs used to treat CVDs target GPCRs. All the evidence demonstrates the crucial role of GPCRs in CVDs. Over the past decades, studies on the structure and function of GPCRs have identified many targets for the treatment of CVDs. In this review, we summarize and discuss the role of GPCRs in the function of the cardiovascular system from both vascular and heart perspectives, then analyze the complex ways in which multiple GPCRs exert regulatory functions in vascular and heart diseases. We hope to provide new ideas for the treatment of CVDs and the development of novel drugs.
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Affiliation(s)
- Yuanqiang Li
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Boyu Li
- Department of Gastroenterology and Hematology, The People's Hospital of Hebi, Henan, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Medicine, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
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Yin X, Yin X, Pan X, Zhang J, Fan X, Li J, Zhai X, Jiang L, Hao P, Wang J, Chen Y. Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention. Front Pharmacol 2023; 14:1070973. [PMID: 37056987 PMCID: PMC10086160 DOI: 10.3389/fphar.2023.1070973] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Cardiac fibrosis plays an indispensable role in cardiac tissue homeostasis and repair after myocardial infarction (MI). The cardiac fibroblast-to-myofibroblast differentiation and extracellular matrix collagen deposition are the hallmarks of cardiac fibrosis, which are modulated by multiple signaling pathways and various types of cells in time-dependent manners. Our understanding of the development of cardiac fibrosis after MI has evolved in basic and clinical researches, and the regulation of fibrotic remodeling may facilitate novel diagnostic and therapeutic strategies, and finally improve outcomes. Here, we aim to elaborate pathophysiology, examination and intervention of cardiac fibrosis after MI.
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Affiliation(s)
- Xiaoying Yin
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xinxin Yin
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xin Pan
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jingyu Zhang
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xinhui Fan
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jiaxin Li
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoxuan Zhai
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Lijun Jiang
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Panpan Hao
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jiali Wang
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Yuguo Chen
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
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Carbone AM, Del Calvo G, Nagliya D, Sharma K, Lymperopoulos A. Autonomic Nervous System Regulation of Epicardial Adipose Tissue: Potential Roles for Regulator of G Protein Signaling-4. Curr Issues Mol Biol 2022; 44:6093-6103. [PMID: 36547076 PMCID: PMC9776453 DOI: 10.3390/cimb44120415] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 11/23/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
The epicardial adipose tissue (EAT) or epicardial fat is a visceral fat depot in the heart that contains intrinsic adrenergic and cholinergic nerves, through which it interacts with the cardiac sympathetic (adrenergic) and parasympathetic (cholinergic) nervous systems. These EAT nerves represent a significant source of several adipokines and other bioactive molecules, including norepinephrine, epinephrine, and free fatty acids. The production of these molecules is biologically relevant for the heart, since abnormalities in EAT secretion are implicated in the development of pathological conditions, including coronary atherosclerosis, atrial fibrillation, and heart failure. Sympathetic hyperactivity and parasympathetic (cholinergic) derangement are associated with EAT dysfunction, leading to a variety of adverse cardiac conditions, such as heart failure, diastolic dysfunction, atrial fibrillation, etc.; therefore, several studies have focused on exploring the autonomic regulation of EAT as it pertains to heart disease pathogenesis and progression. In addition, Regulator of G protein Signaling (RGS)-4 is a protein with significant regulatory roles in both adrenergic and muscarinic receptor signaling in the heart. In this review, we provide an overview of the autonomic regulation of EAT, with a specific focus on cardiac RGS4 and the potential roles this protein plays in this regulation.
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Affiliation(s)
| | | | | | | | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL 33328-2018, USA
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Borges JI, Ferraino KE, Cora N, Nagliya D, Suster MS, Carbone AM, Lymperopoulos A. Adrenal G Protein-Coupled Receptors and the Failing Heart: A Long-distance, Yet Intimate Affair. J Cardiovasc Pharmacol 2022; 80:386-392. [PMID: 34983911 PMCID: PMC9294064 DOI: 10.1097/fjc.0000000000001213] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 12/11/2021] [Indexed: 01/31/2023]
Abstract
Systolic heart failure (HF) is a chronic clinical syndrome characterized by the reduction in cardiac function and still remains the disease with the highest mortality worldwide. Despite considerable advances in pharmacological treatment, HF represents a severe clinical and social burden. Chronic human HF is characterized by several important neurohormonal perturbations, emanating from both the autonomic nervous system and the adrenal glands. Circulating catecholamines (norepinephrine and epinephrine) and aldosterone elevations are among the salient alterations that confer significant hormonal burden on the already compromised function of the failing heart. This is why sympatholytic treatments (such as β-blockers) and renin-angiotensin system inhibitors or mineralocorticoid receptor antagonists, which block the effects of angiotensin II (AngII) and aldosterone on the failing heart, are part of the mainstay HF pharmacotherapy presently. The adrenal gland plays an important role in the modulation of cardiac neurohormonal stress because it is the source of almost all aldosterone, of all epinephrine, and of a significant amount of norepinephrine reaching the failing myocardium from the blood circulation. Synthesis and release of these hormones in the adrenals is tightly regulated by adrenal G protein-coupled receptors (GPCRs), such as adrenergic receptors and AngII receptors. In this review, we discuss important aspects of adrenal GPCR signaling and regulation, as they pertain to modulation of cardiac function in the context of chronic HF, by focusing on the 2 best studied adrenal GPCR types in that context, adrenergic receptors and AngII receptors (AT 1 Rs). Particular emphasis is given to findings from the past decade and a half that highlight the emerging roles of the GPCR-kinases and the β-arrestins in the adrenals, 2 protein families that regulate the signaling and functioning of GPCRs in all tissues, including the myocardium and the adrenal gland.
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Affiliation(s)
- Jordana I. Borges
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Krysten E. Ferraino
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Deepika Nagliya
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Malka S. Suster
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Alexandra M. Carbone
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
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Carbone AM, Borges JI, Suster MS, Sizova A, Cora N, Desimine VL, Lymperopoulos A. Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling. Int J Mol Sci 2022; 23:5803. [PMID: 35628613 PMCID: PMC9147283 DOI: 10.3390/ijms23105803] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/16/2022] [Accepted: 05/20/2022] [Indexed: 02/01/2023] Open
Abstract
Propionic acid is a cell nutrient but also a stimulus for cellular signaling. Free fatty acid receptor (FFAR)-3, also known as GPR41, is a Gi/o protein-coupled receptor (GPCR) that mediates some of the propionate's actions in cells, such as inflammation, fibrosis, and increased firing/norepinephrine release from peripheral sympathetic neurons. The regulator of G-protein Signaling (RGS)-4 inactivates (terminates) both Gi/o- and Gq-protein signaling and, in the heart, protects against atrial fibrillation via calcium signaling attenuation. RGS4 activity is stimulated by β-adrenergic receptors (ARs) via protein kinase A (PKA)-dependent phosphorylation. Herein, we examined whether RGS4 modulates cardiac FFAR3 signaling/function. We report that RGS4 is essential for dampening of FFAR3 signaling in H9c2 cardiomyocytes, since siRNA-mediated RGS4 depletion significantly enhanced propionate-dependent cAMP lowering, Gi/o activation, p38 MAPK activation, pro-inflammatory interleukin (IL)-1β and IL-6 production, and pro-fibrotic transforming growth factor (TGF)-β synthesis. Additionally, catecholamine pretreatment blocked propionic acid/FFAR3 signaling via PKA-dependent activation of RGS4 in H9c2 cardiomyocytes. Finally, RGS4 opposes FFAR3-dependent norepinephrine release from sympathetic-like neurons (differentiated Neuro-2a cells) co-cultured with H9c2 cardiomyocytes, thereby preserving the functional βAR number of the cardiomyocytes. In conclusion, RGS4 appears essential for propionate/FFAR3 signaling attenuation in both cardiomyocytes and sympathetic neurons, leading to cardioprotection against inflammation/adverse remodeling and to sympatholysis, respectively.
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Affiliation(s)
| | | | | | | | | | | | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA; (A.M.C.); (J.I.B.); (M.S.S.); (A.S.); (N.C.); (V.L.D.)
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Lymperopoulos A, Suster MS, Borges JI. Short-Chain Fatty Acid Receptors and Cardiovascular Function. Int J Mol Sci 2022; 23:3303. [PMID: 35328722 PMCID: PMC8952772 DOI: 10.3390/ijms23063303] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/15/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Increasing experimental and clinical evidence points toward a very important role for the gut microbiome and its associated metabolism in human health and disease, including in cardiovascular disorders. Free fatty acids (FFAs) are metabolically produced and utilized as energy substrates during almost every biological process in the human body. Contrary to long- and medium-chain FFAs, which are mainly synthesized from dietary triglycerides, short-chain FFAs (SCFAs) derive from the gut microbiota-mediated fermentation of indigestible dietary fiber. Originally thought to serve only as energy sources, FFAs are now known to act as ligands for a specific group of cell surface receptors called FFA receptors (FFARs), thereby inducing intracellular signaling to exert a variety of cellular and tissue effects. All FFARs are G protein-coupled receptors (GPCRs) that play integral roles in the regulation of metabolism, immunity, inflammation, hormone/neurotransmitter secretion, etc. Four different FFAR types are known to date, with FFAR1 (formerly known as GPR40) and FFAR4 (formerly known as GPR120) mediating long- and medium-chain FFA actions, while FFAR3 (formerly GPR41) and FFAR2 (formerly GPR43) are essentially the SCFA receptors (SCFARs), responding to all SCFAs, including acetic acid, propionic acid, and butyric acid. As with various other organ systems/tissues, the important roles the SCFARs (FFAR2 and FFAR3) play in physiology and in various disorders of the cardiovascular system have been revealed over the last fifteen years. In this review, we discuss the cardiovascular implications of some key (patho)physiological functions of SCFAR signaling pathways, particularly those regulating the neurohormonal control of circulation and adipose tissue homeostasis. Wherever appropriate, we also highlight the potential of these receptors as therapeutic targets for cardiovascular disorders.
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Affiliation(s)
- Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA; (M.S.S.); (J.I.B.)
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Borges JI, Carbone AM, Cora N, Sizova A, Lymperopoulos A. GTPγS Assay for Measuring Agonist-Induced Desensitization of Two Human Polymorphic Alpha 2B-Adrenoceptor Variants. Methods Mol Biol 2022; 2547:267-273. [PMID: 36068469 DOI: 10.1007/978-1-0716-2573-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
α2-Adrenergic receptors (ARs) mediate many cellular actions of epinephrine and norepinephrine, including inhibition of their secretion (sympathetic inhibition) from adrenal chromaffin cells. Like many other G protein-coupled receptors (GPCRs), they undergo agonist-dependent phosphorylation and desensitization by GPCR kinases (GRKs), a phenomenon recently shown to play a major role in the sympathetic overdrive that accompanies and aggravates chronic heart failure. A three-glutamic acid deletion polymorphism in the human α2B-AR subtype gene (Glu301-303) causes impaired agonist-promoted receptor phosphorylation and desensitization, resulting in enhanced signaling to inhibition of cholinergic-induced catecholamine secretion in adrenal chromaffin cells. One of the various pharmacological assays that can be used to quantify and quantitatively compare the degrees of agonist-dependent desensitization, i.e., G protein decoupling, of these two polymorphic α2B-AR variants (or of any two GPCRs for that matter) is the guanosine-5'-O-3-thiotriphosphate (GTPγS) assay that can directly quantify heterotrimeric G protein activation.
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Affiliation(s)
- Jordana I Borges
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Alexandra M Carbone
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Anastasiya Sizova
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA.
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Marsico F, Paolillo S, Gargiulo P, Parisi V, Nappi C, Assante R, Dell'Aversana S, Esposito I, Renga F, Esposito L, Bardi L, Rengo G, Dellegrottaglie S, Marciano C, Leosco D, Cuocolo A, Filardi PP. Renal function and cardiac adrenergic impairment in patients affected by heart failure. J Nucl Cardiol 2021; 28:2112-2122. [PMID: 31808105 DOI: 10.1007/s12350-019-01975-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/20/2019] [Indexed: 01/17/2023]
Abstract
Although in heart failure (HF) there is a strict correlation between heart and kidney, no data are available on the potential relationship in HF between renal dysfunction (RD) and the impaired sympathetic innervation. Aim of the present study was to assess the relationship between RD and cardiac sympathetic innervation in HF patients with reduced ejection fraction. Two hundred and sixty-three patients with mild-to-severe HF underwent iodine-123 meta-iodobenzylguanidine myocardial scintigraphy to assess sympathetic innervation, evaluating early and late heart-to-mediastinum (H/M) ratios and washout rate. In all patients, glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was assessed. A direct association was found between EPI-eGFR and late H/M (r = .215; P < .001). Dividing the population into moderate-to-severe eGFR reduction and normal-to-mildly reduced eGFR (cutoff ≤ 60 mL·min-1·1.73 m-2), a statistically significant reduction of late H/M value was found in patients with RD compared to patients with preserved eGFR (P = .030). By multivariable linear regression analysis, eGFR resulted in the prediction of impaired late H/M in patients with RD (P = .005). Patients with RD and HF show more impaired cardiac sympathetic activity than HF patients with preserved renal function, and reduced eGFR is a predictor of reduced late H/M.
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Affiliation(s)
- Fabio Marsico
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Stefania Paolillo
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Paola Gargiulo
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Valentina Parisi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Carmela Nappi
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Roberta Assante
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Simona Dell'Aversana
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Immacolata Esposito
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Francesco Renga
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Luca Esposito
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Luca Bardi
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Giuseppe Rengo
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | | | | | - Dario Leosco
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Alberto Cuocolo
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy
| | - Pasquale Perrone Filardi
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy.
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Lymperopoulos A, Borges JI, Cora N, Sizova A. Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin's Effects in the Adrenal Gland. Int J Mol Sci 2021; 22:7684. [PMID: 34299304 PMCID: PMC8305388 DOI: 10.3390/ijms22147684] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 12/31/2022] Open
Abstract
Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin's efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.
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Affiliation(s)
- Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA; (J.I.B.); (N.C.); (A.S.)
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13
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Brito AXD, Glavam A, Bronchtein AI, Rosado-de-Castro PH. Autonomic Innervation Evaluation in Cardiac Disease. INTERNATIONAL JOURNAL OF CARDIOVASCULAR SCIENCES 2021. [DOI: 10.36660/ijcs.20200171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Guitart-Mampel M, Urquiza P, Borges JI, Lymperopoulos A, Solesio ME. Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function. Cells 2021; 10:1552. [PMID: 34205363 PMCID: PMC8235589 DOI: 10.3390/cells10061552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/08/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)-particularly βARs-play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.
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Affiliation(s)
- Mariona Guitart-Mampel
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
| | - Pedro Urquiza
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
| | - Jordana I. Borges
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Anastasios Lymperopoulos
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Maria E. Solesio
- Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA; (M.G.-M.); (P.U.)
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Beta-Arrestins in the Treatment of Heart Failure Related to Hypertension: A Comprehensive Review. Pharmaceutics 2021. [DOI: 10.3390/pharmaceutics13060838
expr 929824082 + 956151497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Heart failure (HF) is a complicated clinical syndrome that is considered an increasingly frequent reason for hospitalization, characterized by a complex therapeutic regimen, reduced quality of life, and high morbidity. Long-standing hypertension ultimately paves the way for HF. Recently, there have been improvements in the treatment of hypertension and overall management not limited to only conventional medications, but several novel pathways and their pharmacological alteration are also conducive to the treatment of hypertension. Beta-arrestin (β-arrestin), a protein responsible for beta-adrenergic receptors’ (β-AR) functioning and trafficking, has recently been discovered as a potential regulator in hypertension. β-arrestin isoforms, namely β-arrestin1 and β-arrestin2, mainly regulate cardiac function. However, there have been some controversies regarding the function of the two β-arrestins in hypertension regarding HF. In the present review, we try to figure out the paradox between the roles of two isoforms of β-arrestin in the treatment of HF.
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Rakib A, Eva TA, Sami SA, Mitra S, Nafiz IH, Das A, Tareq AM, Nainu F, Dhama K, Emran TB, Simal-Gandara J. Beta-Arrestins in the Treatment of Heart Failure Related to Hypertension: A Comprehensive Review. Pharmaceutics 2021; 13:838. [PMID: 34198801 PMCID: PMC8228839 DOI: 10.3390/pharmaceutics13060838] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/28/2021] [Accepted: 05/31/2021] [Indexed: 12/24/2022] Open
Abstract
Heart failure (HF) is a complicated clinical syndrome that is considered an increasingly frequent reason for hospitalization, characterized by a complex therapeutic regimen, reduced quality of life, and high morbidity. Long-standing hypertension ultimately paves the way for HF. Recently, there have been improvements in the treatment of hypertension and overall management not limited to only conventional medications, but several novel pathways and their pharmacological alteration are also conducive to the treatment of hypertension. Beta-arrestin (β-arrestin), a protein responsible for beta-adrenergic receptors' (β-AR) functioning and trafficking, has recently been discovered as a potential regulator in hypertension. β-arrestin isoforms, namely β-arrestin1 and β-arrestin2, mainly regulate cardiac function. However, there have been some controversies regarding the function of the two β-arrestins in hypertension regarding HF. In the present review, we try to figure out the paradox between the roles of two isoforms of β-arrestin in the treatment of HF.
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Affiliation(s)
- Ahmed Rakib
- Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (A.R.); (T.A.E.); (S.A.S.)
| | - Taslima Akter Eva
- Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (A.R.); (T.A.E.); (S.A.S.)
| | - Saad Ahmed Sami
- Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (A.R.); (T.A.E.); (S.A.S.)
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh;
| | - Iqbal Hossain Nafiz
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (I.H.N.); (A.D.)
| | - Ayan Das
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh; (I.H.N.); (A.D.)
| | - Abu Montakim Tareq
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh;
| | - Firzan Nainu
- Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Kota Makassar, Sulawesi Selatan 90245, Indonesia;
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India;
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo–Ourense Campus, E32004 Ourense, Spain
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17
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Perez DM. Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure. Int J Mol Sci 2021; 22:5783. [PMID: 34071350 PMCID: PMC8198887 DOI: 10.3390/ijms22115783] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/20/2021] [Accepted: 05/22/2021] [Indexed: 12/14/2022] Open
Abstract
The heart has a reduced capacity to generate sufficient energy when failing, resulting in an energy-starved condition with diminished functions. Studies have identified numerous changes in metabolic pathways in the failing heart that result in reduced oxidation of both glucose and fatty acid substrates, defects in mitochondrial functions and oxidative phosphorylation, and inefficient substrate utilization for the ATP that is produced. Recent early-phase clinical studies indicate that inhibitors of fatty acid oxidation and antioxidants that target the mitochondria may improve heart function during failure by increasing compensatory glucose oxidation. Adrenergic receptors (α1 and β) are a key sympathetic nervous system regulator that controls cardiac function. β-AR blockers are an established treatment for heart failure and α1A-AR agonists have potential therapeutic benefit. Besides regulating inotropy and chronotropy, α1- and β-adrenergic receptors also regulate metabolic functions in the heart that underlie many cardiac benefits. This review will highlight recent studies that describe how adrenergic receptor-mediated metabolic pathways may be able to restore cardiac energetics to non-failing levels that may offer promising therapeutic strategies.
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Affiliation(s)
- Dianne M Perez
- The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
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18
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Lymperopoulos A, Cora N, Maning J, Brill AR, Sizova A. Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe. FEBS J 2021; 288:2645-2659. [PMID: 33599081 DOI: 10.1111/febs.15771] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/02/2021] [Accepted: 02/16/2021] [Indexed: 12/16/2022]
Abstract
The two branches of the autonomic nervous system (ANS), adrenergic and cholinergic, exert a multitude of effects on the human myocardium thanks to the activation of distinct G protein-coupled receptors (GPCRs) expressed on the plasma membranes of cardiac myocytes, cardiac fibroblasts, and coronary vascular endothelial cells. Norepinephrine (NE)/epinephrine (Epi) and acetylcholine (ACh) are released from cardiac ANS terminals and mediate the biological actions of the ANS on the heart via stimulation of cardiac adrenergic or muscarinic receptors, respectively. In addition, several other neurotransmitters/hormones act as facilitators of ANS neurotransmission in the heart, taking part in the so-called nonadrenergic noncholinergic (NANC) part of the ANS's control of cardiac function. These NANC mediators also use several different cell membrane-residing GPCRs to exert their effects in the myocardium. Cardiac ANS dysfunction and an imbalance between the activities of its two branches underlie a variety of cardiovascular diseases, from heart failure and hypertension to coronary artery disease, myocardial ischemia, and arrhythmias. In this review, we present the main well-established signaling modalities used by cardiac autonomic GPCRs, including receptors for salient NANC mediators, and we also highlight the latest developments pertaining to cardiac cell type-specific signal transduction, resulting in cell type-specific cardiac effects of each of these autonomic receptors.
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Affiliation(s)
- Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Jennifer Maning
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Ava R Brill
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Anastasiya Sizova
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA
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Ali DC, Naveed M, Gordon A, Majeed F, Saeed M, Ogbuke MI, Atif M, Zubair HM, Changxing L. β-Adrenergic receptor, an essential target in cardiovascular diseases. Heart Fail Rev 2021; 25:343-354. [PMID: 31407140 DOI: 10.1007/s10741-019-09825-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
β-Adrenergic receptors (βARs) belong to a large family of cell surface receptors known as G protein-coupled receptors (GPCRs). They are coupled to Gs protein (Gαs) for the activation of adenylyl cyclase (AC) yielding cyclic AMP (CAMP), and this provides valuable responses, which can affect the cardiac function such as injury. The binding of an agonist to βAR enhances conformation changes that lead to the Gαs subtype of heterotrimeric G protein which is the AC stimulatory G protein for activation of CAMP in the cells. However, cardiovascular diseases (CVD) have been reported as having an increased rate of death and β1AR, and β2AR are a promising tool that improves the regulatory function in the cardiovascular system (CVS) via signaling. It increases the Gα level, which activates βAR kinase (βARK) that affects and enhances the progression of heart failure (HF) through the activation of cardiomyocyte βARs. We also explained that an increase in GPCR kinases (GRKs) would practically improve the HF pathogenesis and this occurs via the desensitization of βARs, which causes the loss of contractile reserve. The consistency or overstimulation of catecholamines contributes to CVD such as stroke, HF, and cardiac hypertrophy. When there is a decrease in catecholamine responsiveness, it causes aging in old people because the reduction of βAR sensitivity and density in the myocardium enhances downregulation of βARs to AC in the human heart.
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Affiliation(s)
- Daniel Chikere Ali
- Department of Microbiological and Biochemical Pharmacy, School of Life Science, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, People's Republic of China
| | - Muhammad Naveed
- Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, 211166, Nanjing, Jiangsu Province, People's Republic of China
| | - Andrew Gordon
- Department of Pharmacognosy, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, Jiangsu Province, People's Republic of China
| | - Fatima Majeed
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, People's Republic of China
| | - Muhammad Saeed
- Faculty of Animal Production and Technology, The Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 6300, Punjab Province, Pakistan
| | - Michael I Ogbuke
- Department of Pharmacy, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, People's Republic of China
| | - Muhammad Atif
- Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Bahawalpur, 63100, Punjab Province, Pakistan
| | - Hafiz Muhammad Zubair
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, People's Republic of China
| | - Li Changxing
- Department of Human Anatomy, Medical College of Qinghai University, Xining, 810000, Qinghai Province, People's Republic of China.
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Why Do We Not Assess Sympathetic Nervous System Activity in Heart Failure Management: Might GRK2 Serve as a New Biomarker? Cells 2021; 10:cells10020457. [PMID: 33669936 PMCID: PMC7924864 DOI: 10.3390/cells10020457] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/11/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) represents the end-stage condition of several structural and functional cardiovascular diseases, characterized by reduced myocardial pump function and increased pressure load. The dysregulation of neurohormonal systems, especially the hyperactivity of the cardiac adrenergic nervous system (ANS), constitutes a hallmark of HF and exerts a pivotal role in its progression. Indeed, it negatively affects patients’ prognosis, being associated with high morbidity and mortality rates, with a tremendous burden on global healthcare systems. To date, all the techniques proposed to assess the cardiac sympathetic nervous system are burdened by intrinsic limits that hinder their implementation in clinical practice. Several biomarkers related to ANS activity, which may potentially support the clinical management of such a complex syndrome, are slow to be implemented in the routine practice for several limitations due to their assessment and clinical impact. Lymphocyte G-protein-coupled Receptor Kinase 2 (GRK2) levels reflect myocardial β-adrenergic receptor function in HF and have been shown to add independent prognostic information related to ANS overdrive. In the present manuscript, we provide an overview of the techniques currently available to evaluate cardiac ANS in HF and future perspectives in this field of relevant scientific and clinical interest.
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Aparisi Á, Uribarri A. Takotsubo syndrome. Med Clin (Barc) 2020; 155:347-355. [PMID: 32654831 DOI: 10.1016/j.medcli.2020.04.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/08/2023]
Abstract
Takotsubo syndrome is an acute cardiomyopathy that mimics acute coronary syndrome and is characterized by acute heart failure with reversible ventricular motion abnormalities, in the absence of justifying coronary artery disease. This document offers an exhaustive review of various proposed hypotheses that attempt to explain the pathophysiology of this disease and provides an updated review of the different classifications that have emerged in recent years. In addition, we describe the main clinical characteristics of these patients, the diagnostic tests that must be performed and the most appropriate treatment.
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Affiliation(s)
- Álvaro Aparisi
- Departamento de Cardiología, Hospital Clínico Universitario, Valladolid, España
| | - Aitor Uribarri
- Departamento de Cardiología, Hospital Clínico Universitario, Valladolid, España; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, España.
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Cora N, Ghandour J, Pollard CM, Desimine VL, Ferraino KE, Pereyra JM, Valiente R, Lymperopoulos A. Nicotine-induced adrenal beta-arrestin1 upregulation mediates tobacco-related hyperaldosteronism leading to cardiac dysfunction. World J Cardiol 2020; 12:192-202. [PMID: 32547713 PMCID: PMC7283997 DOI: 10.4330/wjc.v12.i5.192] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/27/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tobacco-related products, containing the highly addictive nicotine together with numerous other harmful toxicants and carcinogens, have been clearly associated with coronary artery disease, heart failure, stroke, and other heart diseases. Among the mechanisms by which nicotine contributes to heart disease is elevation of the renin-angiotensin-aldosterone system (RAAS) activity. Nicotine, and its major metabolite in humans cotinine, have been reported to induce RAAS activation, resulting in aldosterone elevation in smokers. Aldosterone has various direct and indirect adverse cardiac effects. It is produced by the adrenal cortex in response to angiotensin II (AngII) activating AngII type 1 receptors. RAAS activity increases in chronic smokers, causing raised aldosterone levels (nicotine exposure causes the same in rats). AngII receptors exert their cellular effects via either G proteins or the two βarrestins (βarrestin1 and-2). AIM Since adrenal ßarrestin1 is essential for adrenal aldosterone production and nicotine/cotinine elevate circulating aldosterone levels in humans, we hypothesized that nicotine activates adrenal ßarrestin1, which contributes to RAAS activation and heart disease development. METHODS We studied human adrenocortical zona glomerulosa H295R cells and found that nicotine and cotinine upregulate βarrestin1 mRNA and protein levels, thereby enhancing AngII-dependent aldosterone synthesis and secretion. RESULTS In contrast, siRNA-mediated βarrestin1 knockdown reversed the effects of nicotine on AngII-induced aldosterone production in H295R cells. Importantly, nicotine promotes hyperaldosteronism via adrenal βarrestin1, thereby precipitating cardiac dysfunction, also in vivo, since nicotine-exposed experimental rats with adrenal-specific βarrestin1 knockdown display lower circulating aldosterone levels and better cardiac function than nicotine-exposed control animals with normal adrenal βarrestin1 expression. CONCLUSION Adrenal βarrestin1 upregulation is one of the mechanisms by which tobacco compounds, like nicotine, promote cardio-toxic hyperaldosteronism in vitro and in vivo. Thus, adrenal βarrestin1 represents a novel therapeutic target for tobacco-related heart disease prevention or mitigation.
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Affiliation(s)
- Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Jennifer Ghandour
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Celina Marie Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Victoria Lynn Desimine
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Krysten Elaine Ferraino
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Janelle Marie Pereyra
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Rachel Valiente
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States.
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Karkoulias G, McCrink KA, Maning J, Pollard CM, Desimine VL, Patsouras N, Psallidopoulos M, Taraviras S, Lymperopoulos A, Flordellis C. Sustained GRK2-dependent CREB activation is essential for α 2-adrenergic receptor-induced PC12 neuronal differentiation. Cell Signal 2020; 66:109446. [PMID: 31678682 DOI: 10.1016/j.cellsig.2019.109446] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/18/2019] [Accepted: 10/21/2019] [Indexed: 12/18/2022]
Abstract
Many aspects of neuronal development, such as neuronal survival and differentiation, are regulated by the transcription factor cAMP-response element-binding protein (CREB). We have previously reported that α2-adrenergic receptors (ARs), members of the G protein-coupled receptor (GPCR) superfamily, induce neuronal differentiation of rat pheochromocytoma (PC)-12 cells in a subtype-specific manner, i.e. α2A<α2B<α2C. Herein, we sought to investigate CREB`s involvement in this α2AR-dependent neurogenic process. We used a combination of gene reporter assays and immunoblotting analysis, coupled with co-immunoprecipitation and morphological analysis, in transfected PC12 cell lines. Chronic α2B- or α2C-AR activation results in sustained CREB activation, which is both necessary and sufficient for neuronal differentiation of PC12 cells expressing these two α2ARs. In contrast, chronic α2A activation only leads to transient CREB activation, insufficient for PC12 neuronal differentiation. However, upon CREB overexpression, α2A-AR triggers neuronal differentiation similarly to α2B- or α2C-ARs. Importantly, NGF (Nerve Growth Factor)`s TrkA receptor transactivation is essential for the sustained activation of CREB by all three α2 subtypes in PC12 cells, whereas protein kinase A (PKA), the prototypic kinase that phosphorylates CREB, is not. Instead, TrkA-activated GPCR-kinase (GRK)-2 mediates the sustained CREB activation during α2AR-induced neuronal differentiation of PC12 cells. In conclusion, catecholaminergic-induced neuronal differentiation of PC12 cells through α2ARs uses a non-canonical pathway involving TrkA transactivation and subsequent GRK2-dependent, sustained phosphorylation/activation of CREB. These findings provide novel insights into catecholaminergic neurogenesis and suggest that α2AR agonists, combined with NGF analogs or GRK2 stimulators, may exert neurogenic/neuroprotective effects.
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Affiliation(s)
- George Karkoulias
- Department of Pharmacology School of Medicine, University of Patras, Patras, Greece
| | - Katie A McCrink
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA
| | - Jennifer Maning
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA
| | - Celina M Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA
| | - Victoria L Desimine
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA
| | - Nicholas Patsouras
- Department of Pharmacology School of Medicine, University of Patras, Patras, Greece
| | | | - Stavros Taraviras
- Department of Physiology, School of Medicine, University of Patras, Patras, Greece
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA.
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Pollard CM, Ghandour J, Cora N, Perez A, Parker BM, Desimine VL, Wertz SL, Pereyra JM, Ferraino KE, Patel JJ, Lymperopoulos A. GRK2-Mediated Crosstalk Between β-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo. Int J Mol Sci 2020; 21:574. [PMID: 31963151 PMCID: PMC7013621 DOI: 10.3390/ijms21020574] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/06/2020] [Accepted: 01/13/2020] [Indexed: 12/13/2022] Open
Abstract
Aldosterone is produced by adrenocortical zona glomerulosa (AZG) cells in response to angiotensin II (AngII) acting through its type I receptors (AT1Rs). AT1R is a G protein-coupled receptor (GPCR) that induces aldosterone via both G proteins and the adapter protein βarrestin1, which binds the receptor following its phosphorylation by GPCR-kinases (GRKs) to initiate G protein-independent signaling. β-adrenergic receptors (ARs) also induce aldosterone production in AZG cells. Herein, we investigated whether GRK2 or GRK5, the two major adrenal GRKs, is involved in the catecholaminergic regulation of AngII-dependent aldosterone production. In human AZG (H295R) cells in vitro, the βAR agonist isoproterenol significantly augmented both AngII-dependent aldosterone secretion and synthesis, as measured by the steroidogenic acute regulatory (StAR) protein and CYP11B2 (aldosterone synthase) mRNA inductions. Importantly, GRK2, but not GRK5, was indispensable for the βAR-mediated enhancement of aldosterone in response to AngII. Specifically, GRK2 inhibition with Cmpd101 abolished isoproterenol's effects on AngII-induced aldosterone synthesis/secretion, whereas the GRK5 knockout via CRISPR/Cas9 had no effect. It is worth noting that these findings were confirmed in vivo, since rats overexpressing GRK2, but not GRK5, in their adrenals had elevated circulating aldosterone levels compared to the control animals. However, treatment with the β-blocker propranolol prevented hyperaldosteronism in the adrenal GRK2-overexpressing rats. In conclusion, GRK2 mediates a βAR-AT1R signaling crosstalk in the adrenal cortex leading to elevated aldosterone production. This suggests that adrenal GRK2 may be a molecular link connecting the sympathetic nervous and renin-angiotensin systems at the level of the adrenal cortex and that its inhibition might be therapeutically advantageous in hyperaldosteronism-related conditions.
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25
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Bencivenga L, Liccardo D, Napolitano C, Visaggi L, Rengo G, Leosco D. β-Adrenergic Receptor Signaling and Heart Failure: From Bench to Bedside. Heart Fail Clin 2019; 15:409-419. [PMID: 31079699 DOI: 10.1016/j.hfc.2019.02.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Despite improvements in management and therapeutic approach in the last decades, heart failure is still associated with high mortality rates. The sustained enhancement in the sympathetic nervous system tone, observed in patients with heart failure, causes alteration in β-adrenergic receptor signaling and function. This latter phenomenon is the result of several heart failure-related molecular abnormalities involving adrenergic receptors, G-protein-coupled receptor kinases, and β-arrestins. This article summarizes novel encouraging preclinical strategies to reactivate β-adrenergic receptor signaling in heart failure, including pharmacologic and gene therapy approaches, and attempts to translate acquired notions into the clinical setting.
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Affiliation(s)
- Leonardo Bencivenga
- Department of Translational Medical Sciences, Division of Geriatrics, Federico II University, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Daniela Liccardo
- Department of Translational Medical Sciences, Division of Geriatrics, Federico II University, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Carmen Napolitano
- Department of Translational Medical Sciences, Division of Geriatrics, Federico II University, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Lucia Visaggi
- Department of Translational Medical Sciences, Division of Geriatrics, Federico II University, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Giuseppe Rengo
- Department of Translational Medical Sciences, Division of Geriatrics, Federico II University, Via Sergio Pansini, 5, Naples 80131, Italy; Istituti Clinici Scientifici Maugeri SpA Società Benefit (ICS Maugeri SpA SB), Telese Terme, Italy
| | - Dario Leosco
- Department of Translational Medical Sciences, Division of Geriatrics, Federico II University, Via Sergio Pansini, 5, Naples 80131, Italy.
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26
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Murga C, Arcones AC, Cruces-Sande M, Briones AM, Salaices M, Mayor F. G Protein-Coupled Receptor Kinase 2 (GRK2) as a Potential Therapeutic Target in Cardiovascular and Metabolic Diseases. Front Pharmacol 2019; 10:112. [PMID: 30837878 PMCID: PMC6390810 DOI: 10.3389/fphar.2019.00112] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 01/28/2019] [Indexed: 12/20/2022] Open
Abstract
G protein-coupled receptor kinase 2 (GRK2) is a central signaling node involved in the modulation of many G protein-coupled receptors (GPCRs) and also displaying regulatory functions in other cell signaling routes. GRK2 levels and activity have been reported to be enhanced in patients or in preclinical models of several relevant pathological situations, such as heart failure, cardiac hypertrophy, hypertension, obesity and insulin resistance conditions, or non-alcoholic fatty liver disease (NAFLD), and to contribute to disease progression by a variety of mechanisms related to its multifunctional roles. Therefore, targeting GRK2 by different strategies emerges as a potentially relevant approach to treat cardiovascular disease, obesity, type 2 diabetes, or NAFLD, pathological conditions which are frequently interconnected and present as co-morbidities.
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Affiliation(s)
- Cristina Murga
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Universidad Autónoma de Madrid, Madrid, Spain.,CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Alba C Arcones
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Universidad Autónoma de Madrid, Madrid, Spain.,CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Marta Cruces-Sande
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Universidad Autónoma de Madrid, Madrid, Spain.,CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Ana M Briones
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.,Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Madrid, Spain.,Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain
| | - Mercedes Salaices
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.,Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Madrid, Spain.,Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain
| | - Federico Mayor
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Universidad Autónoma de Madrid, Madrid, Spain.,CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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27
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Zhang Q, Liu B, Wu Q, Liu B, Li Y, Sun S, Wang Y, Wu X, Chai Z, Jiang X, Liu X, Hu M, Wang Y, Yang Y, Wang L, Kang X, Xiong Y, Zhou Y, Chen X, Zheng L, Zhang B, Wang C, Zhu F, Zhou Z. Differential Co-release of Two Neurotransmitters from a Vesicle Fusion Pore in Mammalian Adrenal Chromaffin Cells. Neuron 2019; 102:173-183.e4. [PMID: 30773347 DOI: 10.1016/j.neuron.2019.01.031] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 10/30/2018] [Accepted: 01/16/2019] [Indexed: 01/12/2023]
Abstract
Co-release of multiple neurotransmitters from secretory vesicles is common in neurons and neuroendocrine cells. However, whether and how the transmitters co-released from a single vesicle are differentially regulated remains unknown. In matrix-containing dense-core vesicles (DCVs) in chromaffin cells, there are two modes of catecholamine (CA) release from a single DCV: quantal and sub-quantal. By combining two microelectrodes to simultaneously record co-release of the native CA and ATP from a DCV, we report that (1) CA and ATP were co-released during a DCV fusion; (2) during kiss-and-run (KAR) fusion, the co-released CA was sub-quantal, whereas the co-released ATP was quantal; and (3) knockdown and knockout of the DCV matrix led to quantal co-release of both CA and ATP even in KAR mode. These findings strongly imply that, in contrast to sub-quantal CA release in chromaffin cells, fast synaptic transmission without transmitter-matrix binding is mediated exclusively via quantal release in neurons.
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Affiliation(s)
- Quanfeng Zhang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Bin Liu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Qihui Wu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Bing Liu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Yinglin Li
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Suhua Sun
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Yuan Wang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Xi Wu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Zuying Chai
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Xiaohan Jiang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Xiaoyao Liu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Meiqin Hu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Yeshi Wang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Yunting Yang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Li Wang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Xinjiang Kang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Yingfei Xiong
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Yang Zhou
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Xiaoke Chen
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Lianghong Zheng
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Bo Zhang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Changhe Wang
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Feipeng Zhu
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Zhuan Zhou
- State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China.
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Wertz SL, Desimine VL, Maning J, McCrink KA, Lymperopoulos A. Co-IP assays for measuring GPCR–arrestin interactions. Methods Cell Biol 2019; 149:205-213. [DOI: 10.1016/bs.mcb.2018.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Desimine VL, McCrink KA, Parker BM, Wertz SL, Maning J, Lymperopoulos A. Biased Agonism/Antagonism of Cardiovascular GPCRs for Heart Failure Therapy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 339:41-61. [PMID: 29776604 DOI: 10.1016/bs.ircmb.2018.02.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
G protein-coupled receptors (GPCRs) are among the most important drug targets currently used in clinic, including drugs for cardiovascular indications. We now know that, in addition to activating heterotrimeric G protein-dependent signaling pathways, GPCRs can also activate G protein-independent signaling, mainly via the βarrestins. The major role of βarrestin1 and -2, also known as arrestin2 or -3, respectively, is to desensitize GPCRs, i.e., uncoupled them from G proteins, and to subsequently internalize the receptor. As the βarrestin-bound GPCR recycles inside the cell, it serves as a signalosome transducing signals in the cytoplasm. Since both G proteins and βarrestins can transduce signals from the same receptor independently of each other, any given GPCR agonist might selectively activate either pathway, which would make it a biased agonist for that receptor. Although this selectivity is always relative (never absolute), in cases where the G protein- and βarrestin-dependent signals emanating from the same GPCR result in different cellular effects, pharmacological exploitation of GPCR-biased agonism might have therapeutic potential. In this chapter, we summarize the GPCR signaling pathways and their biased agonism/antagonism examples discovered so far that can be exploited for heart failure treatment. We also highlight important issues that need to be clarified along the journey of these ligands from bench to the clinic.
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Affiliation(s)
- Victoria L Desimine
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, United States
| | - Katie A McCrink
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, United States
| | - Barbara M Parker
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, United States
| | - Shelby L Wertz
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, United States
| | - Jennifer Maning
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, United States
| | - Anastasios Lymperopoulos
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, United States.
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30
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Arrestins in the Cardiovascular System: An Update. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 159:27-57. [DOI: 10.1016/bs.pmbts.2018.07.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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31
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Maning J, Negussie S, Clark MA, Lymperopoulos A. Biased agonism/antagonism at the AngII-AT1 receptor: Implications for adrenal aldosterone production and cardiovascular therapy. Pharmacol Res 2017; 125:14-20. [PMID: 28511989 DOI: 10.1016/j.phrs.2017.05.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 05/03/2017] [Accepted: 05/11/2017] [Indexed: 12/23/2022]
Abstract
Many of the effects of angiotensin II (AngII), including adrenocortical aldosterone release, are mediated by the AngII type 1 receptor (AT1R), a receptor with essential roles in cardiovascular homeostasis. AT1R belongs to the G protein-coupled receptor (GPCR) superfamily, mainly coupling to the Gq/11 type of G proteins. However, it also signals through βarrestins, oftentimes in parallel to eliciting G protein-dependent signaling. This has spurred infinite possibilities for cardiovascular pharmacology, since various beneficial effects are purportedly exerted by AT1R via βarrestins, unlike AT1R-induced G protein-mediated pathways that usually result in damaging cardiovascular effects, including hypertension and aldosterone elevation. Over the past decade however, a number of studies from our group and others have suggested that AT1R-induced βarrestin signaling can also be damaging for the heart, similarly to the G protein-dependent one, with regard to aldosterone regulation. Additionally, AT1R-induced βarrestin signaling in astrocytes from certain areas of the brain may also play a significant role in central regulation of blood pressure and hypertension pathogenesis. These findings have provided the impetus for testing available angiotensin receptor blockers (ARBs) in their efficacy towards blocking both routes (i.e. both G protein- and βarrestin-dependent) of AT1R signaling in vitro and in vivo and also have promoted structure-activity relationship (SAR) studies for the AngII molecule in terms of βarrestin signaling to certain cellular effects, e.g. adrenal aldosterone production. In the present review, we will recount all of these recent studies on adrenal and astrocyte AT1R-dependent βarrestin signaling while underlining their implications for cardiovascular pathophysiology and therapy.
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Affiliation(s)
- Jennifer Maning
- Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA
| | - Shmuel Negussie
- Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA
| | - Michelle A Clark
- Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA
| | - Anastasios Lymperopoulos
- Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328-2018, USA.
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Lakshmanan R, Maulik N. Development of next generation cardiovascular therapeutics through bio-assisted nanotechnology. J Biomed Mater Res B Appl Biomater 2017; 106:2072-2083. [DOI: 10.1002/jbm.b.34000] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 08/14/2017] [Accepted: 09/01/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Rajesh Lakshmanan
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery; UConn Health; Farmington Connecticut
| | - Nilanjana Maulik
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery; UConn Health; Farmington Connecticut
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Abstract
Originally described by Japanese authors in the 1990s, Takotsubo syndrome (TTS) generally presents as an acute myocardial infarction characterized by severe left ventricular dysfunction. TTS, however, differs from an acute coronary syndrome because patients have generally a normal coronary angiogram and left ventricular dysfunction, which extends beyond the territory subtended by a single coronary artery and recovers within days or weeks. The prognosis was initially thought to be benign, but subsequent studies have demonstrated that both short-term mortality and long-term mortality are higher than previously recognized. Indeed, mortality reported during the acute phase in hospitalized patients is ≈4% to 5%, a figure comparable to that of ST-segment-elevation myocardial infarction in the era of primary percutaneous coronary interventions. Despite extensive research, the cause and pathogenesis of TTS remain incompletely understood. The aim of the present review is to discuss the pathophysiology of TTS with particular emphasis on the role of the central and autonomic nervous systems. Different emotional or psychological stressors have been identified to precede the onset of TTS. The anatomic structures that mediate the stress response are found in both the central and autonomic nervous systems. Acute stressors induce brain activation, increasing bioavailability of cortisol and catecholamine. Both circulating epinephrine and norepinephrine released from adrenal medullary chromaffin cells and norepinephrine released locally from sympathetic nerve terminals are significantly increased in the acute phase of TTS. This catecholamine surge leads, through multiple mechanisms, that is, direct catecholamine toxicity, adrenoceptor-mediated damage, epicardial and microvascular coronary vasoconstriction and/or spasm, and increased cardiac workload, to myocardial damage, which has a functional counterpart of transient apical left ventricular ballooning. The relative preponderance among postmenopausal women suggests that estrogen deprivation may play a facilitating role, probably mediated by endothelial dysfunction. Despite the substantial improvement in our understanding of the pathophysiology of TTS, a number of knowledge gaps remain.
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Affiliation(s)
- Francesco Pelliccia
- From Department of Cardiovascular Sciences, Sapienza University, Rome, Italy (F.P.); Molecular and Clinical Sciences Research Institute, St George's, University of London, UK (J.C.K.); Institute of Cardiology, Catholic University, Rome, Italy (F.C.); and Vita-Salute University and San Raffaele Hospital, Milan, Italy (P.G.C.)
| | - Juan Carlos Kaski
- From Department of Cardiovascular Sciences, Sapienza University, Rome, Italy (F.P.); Molecular and Clinical Sciences Research Institute, St George's, University of London, UK (J.C.K.); Institute of Cardiology, Catholic University, Rome, Italy (F.C.); and Vita-Salute University and San Raffaele Hospital, Milan, Italy (P.G.C.)
| | - Filippo Crea
- From Department of Cardiovascular Sciences, Sapienza University, Rome, Italy (F.P.); Molecular and Clinical Sciences Research Institute, St George's, University of London, UK (J.C.K.); Institute of Cardiology, Catholic University, Rome, Italy (F.C.); and Vita-Salute University and San Raffaele Hospital, Milan, Italy (P.G.C.)
| | - Paolo G Camici
- From Department of Cardiovascular Sciences, Sapienza University, Rome, Italy (F.P.); Molecular and Clinical Sciences Research Institute, St George's, University of London, UK (J.C.K.); Institute of Cardiology, Catholic University, Rome, Italy (F.C.); and Vita-Salute University and San Raffaele Hospital, Milan, Italy (P.G.C.).
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Artalejo AR, Olivos-Oré LA. Alpha2-adrenoceptors in adrenomedullary chromaffin cells: functional role and pathophysiological implications. Pflugers Arch 2017; 470:61-66. [PMID: 28836008 DOI: 10.1007/s00424-017-2059-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Revised: 08/12/2017] [Accepted: 08/15/2017] [Indexed: 12/20/2022]
Abstract
Chromaffin cells from the adrenal medulla participate in stress responses by releasing catecholamines into the bloodstream. Main control of adrenal catecholamine secretion is exerted both neurally (by the splanchnic nerve fibers) and humorally (by corticosteroids, circulating noradrenaline, etc.). It should be noted, however, that secretory products themselves (catecholamines, ATP, opioids, ascorbic acid, chromogranins) could also influence the secretory response in an autocrine/paracrine manner. This form of control is activity-dependent and can be either inhibitory or excitatory. Among the inhibitory influences, it stands out the one mediated by α2-adrenergic autoreceptors activated by released catecholamines. α2-adrenoceptors are G protein-coupled receptors capable to inhibit exocytotic secretion through a direct interaction of Gβγ subunits with voltage-gated Ca2+ channels. Interestingly, upon intense and/or prolonged stimulation, α2-adrenergic receptors become desensitized by the intervention of G protein-coupled receptor kinase 2 (GRK2). In several experimental models of heart failure, there has been reported the up-regulation of GRK2 and the loss of functioning of inhibitory α2-adrenoceptors resulting in enhanced release of adrenomedullary catecholamines. Given the importance of circulating catecholamines in the pathophysiology of heart failure, the recovery of α2-adrenergic modulation of the secretory response from chromaffin cells appears as a novel strategy for a better control of the patients with this cardiac disease.
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Affiliation(s)
- Antonio R Artalejo
- Institute for Research in Neurochemistry & Department of Toxicology and Pharmacology, Faculty of Veterinary, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n, 28029, Madrid, Spain.
| | - Luis Alcides Olivos-Oré
- Institute for Research in Neurochemistry & Department of Toxicology and Pharmacology, Faculty of Veterinary, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n, 28029, Madrid, Spain
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Wang B, Xu M, Li W, Li X, Zheng Q, Niu X. Aerobic exercise protects against pressure overload-induced cardiac dysfunction and hypertrophy via β3-AR-nNOS-NO activation. PLoS One 2017. [PMID: 28622359 PMCID: PMC5473571 DOI: 10.1371/journal.pone.0179648] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Aerobic exercise confers sustainable protection against cardiac hypertrophy and heart failure (HF). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play an important role in exercise-mediated cardioprotection, but the mechanism of NOS/NO stimulation during exercise remains unclear. The aim of this study is to determine the role of β3-adrenergic receptors (β3-ARs), NOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of aerobic exercise. An HF model was constructed by transverse aortic constriction (TAC). Animals were treated with either moderate aerobic exercise by swimming for 9 weeks and/or the β3-AR-specific inhibitor SR59230A at 0.1 mg/kg/hour one day after TAC operation. Myocardial fibrosis, myocyte size, plasma catecholamine (CA) level, cardiac function and geometry were assessed using Masson’s trichrome staining, FITC-labeled wheat germ agglutinin staining, enzyme-linked immuno sorbent assay (ELISA) and echocardiography, respectively. Western blot analysis was performed to elucidate the expression of target proteins. The concentration of myocardial NO production was evaluated using the nitrate reductase method. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD), malonyldialdehyde (MDA), and reactive oxygen species (ROS). Aerobic exercise training improved dilated left ventricular function and partially attenuated the degree of cardiac hypertrophy and fibrosis in TAC mice. Moreover, the increased expression of β3-AR, activation of neuronal NOS (nNOS), and production of NO were detected after aerobic exercise training in TAC mice. However, selective inhibition of β3-AR by SR59230A abolished the upregulation and activation of nNOS induced NO production. Furthermore, aerobic exercise training decreased the myocardial ROS and MDA contents and increased myocardial levels of SOD; both effects were partially attenuated by SR59230A. Our study suggested that aerobic exercise training could improve cardiac systolic function and alleviate LV chamber dilation, cardiac fibrosis and hypertrophy in HF mice. The mechanism responsible for the protective effects of aerobic exercise is associated with the activation of the β3-AR-nNOS-NO pathway.
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Affiliation(s)
- Bin Wang
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Ming Xu
- Department of Physiology, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenju Li
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Xiaoli Li
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Qiangsun Zheng
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
- Department of Cardiology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- * E-mail: (XN); (QZ)
| | - Xiaolin Niu
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
- * E-mail: (XN); (QZ)
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Lymperopoulos A, Aukszi B. Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy. World J Cardiol 2017; 9:200-206. [PMID: 28400916 PMCID: PMC5368669 DOI: 10.4330/wjc.v9.i3.200] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/29/2016] [Accepted: 12/16/2016] [Indexed: 02/06/2023] Open
Abstract
Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II (AngII). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure (HF), is induced by AngII type 1 receptors (AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1 (βarr1) or -2 (βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 protein-independent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers (ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes (G protein-, and βarr1-dependent) at the AngII-activated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by AngII and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-"biased" blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan (and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.
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Affiliation(s)
- Anastasios Lymperopoulos
- Anastasios Lymperopoulos, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, United States
| | - Beatrix Aukszi
- Anastasios Lymperopoulos, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, United States
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Liu CH, Gong Z, Liang ZL, Liu ZX, Yang F, Sun YJ, Ma ML, Wang YJ, Ji CR, Wang YH, Wang MJ, Cui FA, Lin A, Zheng WS, He DF, Qu CX, Xiao P, Liu CY, Thomsen ARB, Joseph Cahill T, Kahsai AW, Yi F, Xiao KH, Xue T, Zhou Z, Yu X, Sun JP. Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling. Nat Commun 2017; 8:14335. [PMID: 28181498 PMCID: PMC5309860 DOI: 10.1038/ncomms14335] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 12/19/2016] [Indexed: 12/22/2022] Open
Abstract
Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by β-arrestins, adaptor molecules that also activate different intracellular signalling pathways. Here we reveal that TRV120027, a β-arrestin-1-biased agonist of the angiotensin II receptor type 1 (AT1R), stimulates acute catecholamine secretion through coupling with the transient receptor potential cation channel subfamily C 3 (TRPC3). We show that TRV120027 promotes the recruitment of TRPC3 or phosphoinositide-specific phospholipase C (PLCγ) to the AT1R-β-arrestin-1 signalling complex. Replacing the C-terminal region of β-arrestin-1 with its counterpart on β-arrestin-2 or using a specific TAT-P1 peptide to block the interaction between β-arrestin-1 and PLCγ abolishes TRV120027-induced TRPC3 activation. Taken together, our results show that the GPCR-arrestin complex initiates non-desensitized signalling at the plasma membrane by coupling with ion channels. This fast communication pathway might be a common mechanism of several cellular processes.
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Affiliation(s)
- Chun-Hua Liu
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
- Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China
- Department of Physiology, Taishan Medical University, Taian, Shandong 271000, China
| | - Zheng Gong
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Zong-Lai Liang
- Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Zhi-Xin Liu
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Fan Yang
- Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Yu-Jing Sun
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Ming-Liang Ma
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Yi-Jing Wang
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Chao-Ran Ji
- Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Yu-Hong Wang
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Mei-Jie Wang
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Fu-Ai Cui
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Amy Lin
- Duke University, School of Medicine, Durham, North Carolina 27705, USA
| | - Wen-Shuai Zheng
- Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Dong-Fang He
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
- Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Chang-xiu Qu
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
- Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Peng Xiao
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Chuan-Yong Liu
- Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | | | | | - Alem W. Kahsai
- Duke University, School of Medicine, Durham, North Carolina 27705, USA
| | - Fan Yi
- Department of Pharmacology, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Kun-Hong Xiao
- Duke University, School of Medicine, Durham, North Carolina 27705, USA
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
| | - Tian Xue
- Hefei National Laboratory for Physical Science at Microscale, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Zhuan Zhou
- Laboratory of Cellular Biophysics and Neurodegeneration, Ying-Jie Conference Center, Peking University, Beijing 100871, China
| | - Xiao Yu
- Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China
| | - Jin-Peng Sun
- Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
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Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies. Biochim Biophys Acta Mol Basis Dis 2017; 1863:1883-1892. [PMID: 28130200 DOI: 10.1016/j.bbadis.2017.01.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 01/13/2017] [Accepted: 01/18/2017] [Indexed: 02/06/2023]
Abstract
The pathologic crosstalk between the heart and kidney is known as cardiorenal syndrome (CRS). While the specific mechanisms underlying this crosstalk remain poorly understood, CRS is associated with exacerbated dysfunction of either or both organs and reduced survival. Maladaptive fibrotic remodeling is a key component of both heart and kidney failure pathogenesis and progression. G-protein coupled receptor (GPCR) signaling is a crucial regulator of cardiovascular and renal function. Chronic/pathologic GPCR signaling elicits the interaction of the G-protein Gβγ subunit with GPCR kinase 2 (GRK2), targeting the receptor for internalization, scaffolding to pathologic signals, and receptor degradation. Targeting this pathologic Gβγ-GRK2 interaction has been suggested as a possible strategy for the treatment of HF. In the current review, we discuss recent updates in understanding the role of GPCR-Gβγ-GRK2 signaling as a crucial mediator of maladaptive organ remodeling detected in HF and kidney dysfunction, with specific attention to small molecule-mediated inhibition of pathologic Gβγ-GRK2 interactions. Further, we explore the potential of GPCR-Gβγ-GRK2 signaling as a possible therapeutic target for cardiorenal pathologies.
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Mody R, Hernandez Y, Lymperopoulos A. Assays of adrenal GPCR signaling and regulation: Measuring adrenal β-arrestin activity in vivo through plasma membrane recruitment. Methods Cell Biol 2017:79-87. [DOI: 10.1016/bs.mcb.2017.07.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Selective Blockade of α 2-Adrenoceptor Subtypes Modulates Contractility of Rat Myocardium. Bull Exp Biol Med 2016; 162:177-179. [PMID: 27909967 DOI: 10.1007/s10517-016-3569-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Indexed: 10/20/2022]
Abstract
The study examined the dose-dependent effects of selective antagonists of α2A/D-, α2B-, and α2C- adrenoceptors applied in concentrations of 10-9-10-5 M on atrial and ventricular contractility of rat myocardium in vitro. Selective blockade of each α2-adrenoceptor subtype affected the contractile force of the atrial and ventricular strips. Various concentrations of α2A/D- and α2C-adrenoceptor antagonists produced positive inotropic effect on ventricular strips and negative effect on atrial strips. α2B-Adrenoceptor blocker in the majority of the tested concentrations produced a positive inotropic effect in both atria and ventricles.
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Lymperopoulos A, Brill A, McCrink KA. GPCRs of adrenal chromaffin cells & catecholamines: The plot thickens. Int J Biochem Cell Biol 2016; 77:213-219. [PMID: 26851510 DOI: 10.1016/j.biocel.2016.02.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Revised: 02/01/2016] [Accepted: 02/02/2016] [Indexed: 12/14/2022]
Abstract
The circulating catecholamines (CAs) epinephrine (Epi) and norepinephrine (NE) derive from two major sources in the whole organism: the sympathetic nerve endings, which release NE on effector organs, and the chromaffin cells of the adrenal medulla, which are cells that synthesize, store and release Epi (mainly) and NE. All of the Epi in the body and a significant amount of circulating NE derive from the adrenal medulla. The secretion of CAs from adrenal chromaffin cells is regulated in a complex way by a variety of membrane receptors, the vast majority of which are G protein-coupled receptors (GPCRs), including adrenergic receptors (ARs), which act as "presynaptic autoreceptors" in this regard. There is a plethora of CA-secretagogue signals acting on these receptors but some of them, most notably the α2ARs, inhibit CA secretion. Over the past few years, however, a few new proteins present in chromaffin cells have been uncovered to participate in CA secretion regulation. Most prominent among these are GRK2 and β-arrestin1, which are known to interact with GPCRs regulating receptor signaling and function. The present review will discuss the molecular and signaling mechanisms by which adrenal chromaffin cell-residing GPCRs and their regulatory proteins modulate CA synthesis and secretion. Particular emphasis will be given to the newly discovered roles of GRK2 and β-arrestins in these processes and particular points of focus for future research will be highlighted, as well.
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Affiliation(s)
- Anastasios Lymperopoulos
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, College of Pharmacy, 3200 S. University Dr., Fort Lauderdale, FL 33328-2018, USA.
| | - Ava Brill
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, College of Pharmacy, 3200 S. University Dr., Fort Lauderdale, FL 33328-2018, USA
| | - Katie A McCrink
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, College of Pharmacy, 3200 S. University Dr., Fort Lauderdale, FL 33328-2018, USA
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Hullmann J, Traynham CJ, Coleman RC, Koch WJ. The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development. Pharmacol Res 2016; 110:52-64. [PMID: 27180008 DOI: 10.1016/j.phrs.2016.05.008] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 05/05/2016] [Indexed: 12/11/2022]
Abstract
Heart failure (HF) is a global epidemic with the highest degree of mortality and morbidity of any disease presently studied. G protein-coupled receptors (GPCRs) are prominent regulators of cardiovascular function. Activated GPCRs are "turned off" by GPCR kinases (GRKs) in a process known as "desensitization". GRKs 2 and 5 are highly expressed in the heart, and known to be upregulated in HF. Over the last 20 years, both GRK2 and GRK5 have been demonstrated to be critical mediators of the molecular alterations that occur in the failing heart. In the present review, we will highlight recent findings that further characterize "non-canonical" GRK signaling observed in HF. Further, we will also present potential therapeutic strategies (i.e. small molecule inhibition, microRNAs, gene therapy) that may have potential in combating the deleterious effects of GRKs in HF.
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Affiliation(s)
| | - Christopher J Traynham
- Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, United States
| | - Ryan C Coleman
- Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, United States
| | - Walter J Koch
- Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, United States.
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Jafferjee M, Reyes Valero T, Marrero C, McCrink KA, Brill A, Lymperopoulos A. GRK2 Up-Regulation Creates a Positive Feedback Loop for Catecholamine Production in Chromaffin Cells. Mol Endocrinol 2016; 30:372-381. [PMID: 26849467 PMCID: PMC5414648 DOI: 10.1210/me.2015-1305] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 02/03/2016] [Indexed: 12/15/2022] Open
Abstract
Elevated sympathetic nervous system (SNS) activity aggravates several diseases, including heart failure. The molecular cause(s) underlying this SNS hyperactivity are not known. We have previously uncovered a neurohormonal mechanism, operating in adrenomedullary chromaffin cells, by which circulating catecholamine (CA) levels increase in heart failure: severe dysfunction of the adrenal α2-adrenergic receptors (ARs) due to the up-regulation of G protein-coupled receptor-kinase (GRK)-2, the kinase that desensitizes them. Herein we looked at the potential signaling mechanisms that bring about this GRK2 elevation in chromaffin cells. We found that chronic CA treatment of either PC12 or rat primary chromaffin cells can in itself result in GRK2 transcriptional up-regulation through α2ARs-Gi/o proteins-Src-ERK1/2. The resultant GRK2 increase severely enhances the α2AR desensitization/down-regulation elevating not only CA release but also CA biosynthesis, as evidenced by tyrosine hydroxylase up-regulation. Finally, GRK2 knockdown leads to enhanced apoptosis of PC12 cells, indicating an essential role for GRK2 in chromaffin cell homeostasis/survival. In conclusion, chromaffin cell GRK2 mediates a positive feedback loop that feeds into CA secretion, thereby enabling the adrenomedullary component of the SNS to turn itself on.
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Affiliation(s)
- Malika Jafferjee
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, Florida 33328-2018
| | - Thairy Reyes Valero
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, Florida 33328-2018
| | - Christine Marrero
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, Florida 33328-2018
| | - Katie A McCrink
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, Florida 33328-2018
| | - Ava Brill
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, Florida 33328-2018
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft Lauderdale, Florida 33328-2018
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Rengo G, Pagano G, Filardi PP, Femminella GD, Parisi V, Cannavo A, Liccardo D, Komici K, Gambino G, D'Amico ML, de Lucia C, Paolillo S, Trimarco B, Vitale DF, Ferrara N, Koch WJ, Leosco D. Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure. Circ Res 2016; 118:1116-24. [PMID: 26884616 DOI: 10.1161/circresaha.115.308207] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/16/2016] [Indexed: 01/08/2023]
Abstract
RATIONALE Sympathetic nervous system hyperactivity is associated with poor prognosis in patients with heart failure (HF), yet routine assessment of sympathetic nervous system activation is not recommended for clinical practice. Myocardial G protein-coupled receptor kinase-2 (GRK2) is upregulated in HF patients, causing dysfunctional β-adrenergic receptor signaling. Importantly, myocardial GRK2 levels correlate with levels found in peripheral lymphocytes of HF patients. OBJECTIVE The independent prognostic value of blood GRK2 measurements in HF patients has never been investigated; thus, the purpose of this study was to evaluate whether lymphocyte GRK2 levels predict clinical outcome in HF patients. METHODS AND RESULTS We prospectively studied 257 HF patients with mean left ventricular ejection fraction of 31.4±8.5%. At the time of enrollment, plasma norepinephrine, serum NT-proBNP, and lymphocyte GRK2 levels, as well as clinical and instrumental variables were measured. The prognostic value of GRK2 to predict cardiovascular (CV) death and all-cause mortality was assessed using the Cox proportional hazard model including demographic, clinical, instrumental, and laboratory data. Over a mean follow-up period of 37.5±20.2 months (range, 3-60 months), there were 102 CV deaths. Age, left ventricular ejection fraction, New York Heart Association class, chronic obstructive pulmonary disease, chronic kidney disease, N-terminal-pro brain natriuretic peptide, and lymphocyte GRK2 protein levels were independent predictors of CV mortality in HF patients. GRK2 levels showed an additional prognostic and clinical value over demographic and clinical variables. The independent prognostic value of lymphocyte GRK2 levels was also confirmed for all-cause mortality. CONCLUSIONS Lymphocyte GRK2 protein levels can independently predict prognosis in patients with HF.
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Affiliation(s)
- Giuseppe Rengo
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Gennaro Pagano
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Pasquale Perrone Filardi
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Grazia Daniela Femminella
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Valentina Parisi
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Alessandro Cannavo
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Daniela Liccardo
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Klara Komici
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Giuseppina Gambino
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Maria Loreta D'Amico
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Claudio de Lucia
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Stefania Paolillo
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Bruno Trimarco
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Dino Franco Vitale
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Nicola Ferrara
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.)
| | - Walter J Koch
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
| | - Dario Leosco
- From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
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Peculiar Effects of Selective Blockade of α2-Adrenoceptor Subtypes on Cardiac Chronotropy in Newborn Rats. Bull Exp Biol Med 2015; 160:6-8. [DOI: 10.1007/s10517-015-3084-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Indexed: 10/22/2022]
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Effect of Selective Blockade of α2C-Adrenoceptors on Cardiac Activity in Growing Rats. Bull Exp Biol Med 2015; 159:697-9. [PMID: 26519277 DOI: 10.1007/s10517-015-3051-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Indexed: 10/22/2022]
Abstract
Selective blockade of α2C-adrenoceptors had different effects on the cardiovascular system in rats of various age groups. Blockade of α2C-adrenoceptors in adult rats and 3-week-old animals produced the positive and negative chronotropic effects, respectively. HR in 1-week-old and 6-week-old rats did not change during α2C-adrenoceptor blockade. Selective blockade of α2C-adrenoceptors in adult rats and 3-week-old animals was followed by the increase in BP. BP in 6-week-old rats was shown to decrease under these conditions.
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McCrink KA, Brill A, Lymperopoulos A. Adrenal G protein-coupled receptor kinase-2 in regulation of sympathetic nervous system activity in heart failure. World J Cardiol 2015; 7:539-543. [PMID: 26413230 PMCID: PMC4577680 DOI: 10.4330/wjc.v7.i9.539] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 06/24/2015] [Accepted: 07/11/2015] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF), the number one cause of death in the western world, is caused by the insufficient performance of the heart leading to tissue underperfusion in response to an injury or insult. It comprises complex interactions between important neurohormonal mechanisms that try but ultimately fail to sustain cardiac output. The most prominent such mechanism is the sympathetic (adrenergic) nervous system (SNS), whose activity and outflow are greatly elevated in HF. SNS hyperactivity confers significant toxicity to the failing heart and markedly increases HF morbidity and mortality via excessive activation of adrenergic receptors, which are G protein-coupled receptors. Thus, ligand binding induces their coupling to heterotrimeric G proteins that transduce intracellular signals. G protein signaling is turned-off by the agonist-bound receptor phosphorylation courtesy of G protein-coupled receptor kinases (GRKs), followed by βarrestin binding, which prevents the GRK-phosphorylated receptor from further interaction with the G proteins and simultaneously leads it inside the cell (receptor sequestration). Recent evidence indicates that adrenal GRK2 and βarrestins can regulate adrenal catecholamine secretion, thereby modulating SNS activity in HF. The present review gives an account of all these studies on adrenal GRKs and βarrestins in HF and discusses the exciting new therapeutic possibilities for chronic HF offered by targeting these proteins pharmacologically.
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Affiliation(s)
- Katie A McCrink
- Katie A McCrink, Ava Brill, Anastasios Lymperopoulos, Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL 33328-2018, United States
| | - Ava Brill
- Katie A McCrink, Ava Brill, Anastasios Lymperopoulos, Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL 33328-2018, United States
| | - Anastasios Lymperopoulos
- Katie A McCrink, Ava Brill, Anastasios Lymperopoulos, Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL 33328-2018, United States
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Capote LA, Mendez Perez R, Lymperopoulos A. GPCR signaling and cardiac function. Eur J Pharmacol 2015; 763:143-148. [PMID: 25981298 DOI: 10.1016/j.ejphar.2015.05.019] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 03/30/2015] [Accepted: 05/11/2015] [Indexed: 12/27/2022]
Abstract
G protein-coupled receptors (GPCRs), such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, i.e. myocytes, fibroblasts and endothelial cells, play crucial roles in regulating cardiac function and morphology. Their importance in cardiac physiology and disease is reflected by the fact that, collectively, they represent the direct targets of over a third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of their structure, function and the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart disease therapy. Here, we review these signaling modalities employed by GPCRs known to be expressed in the cardiac myocyte membranes and to directly modulate cardiac contractility. We also highlight drugs and drug classes that directly target these GPCRs to modulate cardiac function, as well as molecules involved in cardiac GPCR signaling that have the potential of becoming novel drug targets for modulation of cardiac function in the future.
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Affiliation(s)
- Leany A Capote
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA
| | - Roberto Mendez Perez
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA
| | - Anastasios Lymperopoulos
- From the Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA.
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Alterations of left ventricular deformation and cardiac sympathetic derangement in patients with systolic heart failure: a 3D speckle tracking echocardiography and cardiac ¹²³I-MIBG study. Eur J Nucl Med Mol Imaging 2015; 42:1601-11. [PMID: 25947572 DOI: 10.1007/s00259-015-3054-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 03/19/2015] [Indexed: 12/29/2022]
Abstract
PURPOSE Myocardial contractile function is under the control of cardiac sympathetic activity. Three-dimensional speckle tracking echocardiography (3D-STE) and cardiac imaging with (123)I-metaiodobenzylguanidine ((123)I-MIBG) are two sophisticated techniques for the assessment of left ventricular (LV) deformation and sympathetic innervation, respectively, which offer important prognostic information in patients with heart failure (HF). The purpose of this investigation was to explore, in patients with systolic HF, the relationship between LV deformation assessed by 3D-STE and cardiac sympathetic derangement evaluated by (123)I-MIBG imaging. METHODS We prospectively studied 75 patients with systolic HF. All patients underwent a 3D-STE study (longitudinal, circumferential, area and radial) and (123)I-MIBG planar and SPECT cardiac imaging. RESULTS 3D-STE longitudinal, circumferential and area strain values were correlated with (123)I-MIBG late heart to mediastinum (H/M) ratio and late SPECT total defect score. After stratification of the patients according to ischaemic or nonischaemic HF aetiology, we observed a good correlation of all 3D-STE measurements with late H/M ratio and SPECT data in the ischaemic group, but in patients with HF of nonischaemic aetiology, no correlation was found between LV deformation and cardiac sympathetic activity. At the regional level, the strongest correlation between LV deformation and adrenergic innervation was found for the left anterior descending coronary artery distribution territory for all four 3D-STE values. In multivariate linear regression analyses, including age, gender, LV ejection fraction, NYHA class, body mass index, heart rate and HF aetiology, only 3D-STE area and radial strain values significantly predicted cardiac sympathetic derangement on (123)I-MIBG late SPECT. CONCLUSION This study indicated that 3D-STE measurements are correlated with (123)I-MIBG planar and SPECT data. Furthermore, 3D-STE area and radial strain values, but not LVEF, predict cardiac sympathetic derangement in human postischaemic HF.
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Effect of Selective Blockade of α2-Adrenoceptor Subtypes on Cardiovascular System in Rats. Bull Exp Biol Med 2015; 158:410-2. [DOI: 10.1007/s10517-015-2774-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Indexed: 11/26/2022]
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