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1
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Neumann J, Hofmann B, Gergs U. Ubrogepant, erenumab, and eptinezumab antagonize positive inotropic effects of the calcitonin gene-related peptide in the isolated human atrium. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04029-7. [PMID: 40085216 DOI: 10.1007/s00210-025-04029-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Accepted: 03/06/2025] [Indexed: 03/16/2025]
Abstract
The calcitonin gene-related peptide (CGRP) is an endogenous peptide that is known to be involved in the development of a migraine. CGRP is also present in the human heart, acts via CGRP receptors, and has been shown to increase the force of contraction (FOC) in isolated, electrically driven human atrial preparations (HAP) from adult patients obtained during open-heart surgery. Here, the hypothesis was tested that the positive inotropic effect (PIE) of CGRP could be attenuated by three anti-migraine drugs, namely ubrogepant, erenumab (both CGRP receptor antagonists), and eptinezumab (a CGRP antagonist). CGRP, cumulatively applied at concentrations ranging from 1 to 100 nM, increased the FOC. In the presence of cilostamide, an inhibitor of phosphodiesterase III, CGRP was more potent and effective than in the absence of cilostamide. Furthermore, when 100 nM CGRP was administered, subsequent application of ubrogepant (1 nM), erenumab (2 nM), and eptinezumab (6 nM) led to a reduction of FOC in HAP. In a more effective way, 1 µM carbachol and 1 µM (-)-N6-phenylisopropyladenosine (PIA) attenuated the PIE of CGRP in the presence of cilostamide. Conversely, when we applied first ubrogepant (1 nM), erenumab (2 nM), or eptinezumab (6 nM), then, this pre-incubation attenuated the PIE in HAP of cumulatively applied CGRP compared to CGRP given alone. We conclude that ubrogepant, erenumab, and eptinezumab are functional antagonists of CGRP in HAP at therapeutic concentrations of these anti-migraine drugs. Further investigation is necessary to determine whether this reduction in FOC is beneficial or detrimental for migraine patients.
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Affiliation(s)
- Joachim Neumann
- Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Magdeburger Straße 4, Halle, Saale, D-06112, Germany.
| | - Britt Hofmann
- Department of Cardiac Surgery, mid-German Heart Center, University Hospital Halle, Ernst-Grube-Straße 40, Halle, Saale, D-06097, Germany
| | - Ulrich Gergs
- Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Magdeburger Straße 4, Halle, Saale, D-06112, Germany
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2
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Manolis D, Hasan S, Maraveyas A, O'Brien DP, Kessler BM, Kramer H, Nikitenko LL. Quantitative proteomics reveals CLR interactome in primary human cells. J Biol Chem 2024; 300:107399. [PMID: 38777147 PMCID: PMC11231609 DOI: 10.1016/j.jbc.2024.107399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 05/03/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
The G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) mediates essential functions in several cell types and is implicated in cardiovascular pathologies, skin diseases, migraine, and cancer. To date, the network of proteins interacting with CLR ("CLR interactome") in primary cells, where this GPCR is expressed at endogenous (physiologically relevant) levels, remains unknown. To address this knowledge gap, we established a novel integrative methodological workflow/approach for conducting a comprehensive/proteome-wide analysis of Homo sapiens CLR interactome. We used primary human dermal lymphatic endothelial cells and combined immunoprecipitation utilizing anti-human CLR antibody with label-free quantitative nano LC-MS/MS and quantitative in situ proximity ligation assay. By using this workflow, we identified 37 proteins interacting with endogenously expressed CLR amongst 4902 detected members of the cellular proteome (by quantitative nano LC-MS/MS) and revealed direct interactions of two kinases and two transporters with this GPCR (by in situ proximity ligation assay). All identified interactors have not been previously reported as members of CLR interactome. Our approach and findings uncover the hitherto unrecognized compositional complexity of the interactome of endogenously expressed CLR and contribute to fundamental understanding of the biology of this GPCR. Collectively, our study provides a first-of-its-kind integrative methodological approach and datasets as valuable resources and robust platform/springboard for advancing the discovery and comprehensive characterization of physiologically relevant CLR interactome at a proteome-wide level in a range of cell types and diseases in future studies.
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Affiliation(s)
- Dimitrios Manolis
- Centre for Biomedicine, Hull York Medical School, University of Hull, Hull, UK
| | - Shirin Hasan
- Centre for Biomedicine, Hull York Medical School, University of Hull, Hull, UK
| | - Anthony Maraveyas
- Queens Centre for Oncology and Haematology, Castle Hill Hospital, Hull University Teaching Hospitals NHS Teaching Trust, Hull, UK
| | - Darragh P O'Brien
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Benedikt M Kessler
- Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Holger Kramer
- Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
| | - Leonid L Nikitenko
- Centre for Biomedicine, Hull York Medical School, University of Hull, Hull, UK.
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3
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Huang T, Su J, Wang X, Shi N, Zhang X, He J, Li J, Zhang J, Wang Y. Functional Analysis and Tissue-Specific Expression of Calcitonin and CGRP with RAMP-Modulated Receptors CTR and CLR in Chickens. Animals (Basel) 2024; 14:1058. [PMID: 38612299 PMCID: PMC11010885 DOI: 10.3390/ani14071058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/18/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Calcitonin (CT) and calcitonin gene-related peptide (CGRP) are critical regulators of calcium balance and have extensive implications for vertebrate physiological processes. This study explores the CT and CGRP signaling systems in chickens through cloning and characterization of the chicken calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR), together with three receptor activity-modifying proteins (RAMPs). We illuminated the functional roles for chickens between the receptors examined alone and in RAMP-associated complexes using luciferase reporter assays. Chicken CTRs and CLRs stimulated the cAMP/PKA and MAPK/ERK signaling pathways, signifying their functional receptor status, with CT showing appreciable ligand activity at nanomolar concentrations across receptor combinations. Notably, it is revealed that chicken CLR can act as a functional receptor for CT without or with RAMPs. Furthermore, we uncovered a tissue-specific expression profile for CT, CGRP, CTR, CLR, and RAMPs in chickens, indicating the different physiological roles across various tissues. In conclusion, our data establish a clear molecular basis to reveal information on CT, CGRP, CTR, CLR, and RAMPs in chickens and contribute to understanding the conserved or divergent functions of this family in vertebrates.
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Affiliation(s)
| | | | | | | | | | | | | | - Jiannan Zhang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610065, China; (T.H.)
| | - Yajun Wang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610065, China; (T.H.)
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4
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Bálint L, Nelson-Maney N, Tian Y, Serafin DS, Caron KM. Clinical Potential of Adrenomedullin Signaling in the Cardiovascular System. Circ Res 2023; 132:1185-1202. [PMID: 37104556 PMCID: PMC10155262 DOI: 10.1161/circresaha.123.321673] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 03/16/2023] [Indexed: 04/29/2023]
Abstract
Numerous clinical studies have revealed the utility of circulating AM (adrenomedullin) or MR-proAM (mid-regional proAM 45-92) as an effective prognostic and diagnostic biomarker for a variety of cardiovascular-related pathophysiologies. Thus, there is strong supporting evidence encouraging the exploration of the AM-CLR (calcitonin receptor-like receptor) signaling pathway as a therapeutic target. This is further bolstered because several drugs targeting the shared CGRP (calcitonin gene-related peptide)-CLR pathway are already Food and Drug Administration-approved and on the market for the treatment of migraine. In this review, we summarize the AM-CLR signaling pathway and its modulatory mechanisms and provide an overview of the current understanding of the physiological and pathological roles of AM-CLR signaling and the yet untapped potentials of AM as a biomarker or therapeutic target in cardiac and vascular diseases and provide an outlook on the recently emerged strategies that may provide further boost to the possible clinical applications of AM signaling.
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Affiliation(s)
- László Bálint
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
| | - Nathan Nelson-Maney
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
| | - Yanna Tian
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
| | - D. Stephen Serafin
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
| | - Kathleen M. Caron
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill; 111 Mason Farm Road, Chapel Hill, North Carolina, USA 27599
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5
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Uehara Y, Tanaka Y, Zhao S, Nikolaidis NM, Pitstick LB, Wu H, Yu JJ, Zhang E, Hasegawa Y, Noel JG, Gardner JC, Kopras EJ, Haffey WD, Greis KD, Guo J, Woods JC, Wikenheiser-Brokamp KA, Kyle JE, Ansong C, Teitelbaum SL, Inoue Y, Altinişik G, Xu Y, McCormack FX. Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis. Nat Commun 2023; 14:1205. [PMID: 36864068 PMCID: PMC9981730 DOI: 10.1038/s41467-023-36810-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 02/17/2023] [Indexed: 03/04/2023] Open
Abstract
Pulmonary alveolar microlithiasis is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a pulmonary alveolar microlithiasis lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes and other proteins suggested a role for osteoclast-like cells in the host response to microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activation in a receptor activator of nuclear factor-κB ligand and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.
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Affiliation(s)
- Yasuaki Uehara
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Yusuke Tanaka
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Shuyang Zhao
- Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Nikolaos M Nikolaidis
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lori B Pitstick
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Huixing Wu
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jane J Yu
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Erik Zhang
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Yoshihiro Hasegawa
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - John G Noel
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jason C Gardner
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Elizabeth J Kopras
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Wendy D Haffey
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Kenneth D Greis
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jinbang Guo
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Jason C Woods
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | | | - Jennifer E Kyle
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Charles Ansong
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Steven L Teitelbaum
- Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA
| | - Yoshikazu Inoue
- Department of Diffuse Lung Diseases and Respiratory Failure, Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan
| | - Göksel Altinişik
- Department of Chest Diseases, Faculty of Medicine, Pamukkale University, Pamukkale, Turkey
| | - Yan Xu
- Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Departments of Pediatrics and Biomedical Informatics, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
| | - Francis X McCormack
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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6
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Procalcitonin and Adrenomedullin in Infectious Diseases. MICROBIOLOGY RESEARCH 2023. [DOI: 10.3390/microbiolres14010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Calcitonin (CT) and adrenomedullin (ADM) are members of the CT family. Procalcitonin (PCT) is a prohormone of CT. Elevations in serum PCT and ADM levels are associated with severe sepsis and coronavirus disease 2019 (COVID-19). PCT enhances sepsis mortality and it binds to the CGRP receptor, which is a heterodimer of CT receptor-like receptor and receptor activity-modifying protein 1. The N-terminal truncated form of PCT, PCT3-116, is produced by the cleavage of PCT by dipeptidyl peptidase 4 (DPP-4) and is the main form of PCT in serum during sepsis, inducing microvascular permeability. Mid-regional pro-adrenomedullin (MR-proADM) is used instead of ADM as a biological indicator because ADM is rapidly degraded, and MR-proADM is released at the same rate as ADM. ADM reduces endothelial permeability and promotes endothelial stability. Endothelial dysfunction is responsible for multiple organ failure in sepsis and COVID-19 patients. Therefore, ADM may be an important molecule for improving the severity associated with sepsis and COVID-19. This review focuses on the current knowledge of PCT and ADM in sepsis and COVID-19.
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7
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The impact of perceived stress on the hair follicle: Towards solving a psychoneuroendocrine and neuroimmunological puzzle. Front Neuroendocrinol 2022; 66:101008. [PMID: 35660551 DOI: 10.1016/j.yfrne.2022.101008] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 05/03/2022] [Accepted: 05/24/2022] [Indexed: 12/24/2022]
Abstract
While popular belief harbors little doubt that perceived stress can cause hair loss and premature graying, the scientific evidence for this is arguably much thinner. Here, we investigate whether these phenomena are real, and show that the cyclic growth and pigmentation of the hair follicle (HF) provides a tractable model system for dissecting how perceived stress modulates aspects of human physiology. Local production of stress-associated neurohormones and neurotrophins coalesces with neurotransmitters and neuropeptides released from HF-associated sensory and autonomic nerve endings, forming a complex local stress-response system that regulates perifollicular neurogenic inflammation, interacts with the HF microbiome and controls mitochondrial function. This local system integrates into the central stress response systems, allowing the study of systemic stress responses affecting organ function by quantifying stress mediator content of hair. Focusing on selected mediators in this "brain-HF axis" under stress conditions, we distill general principles of HF dysfunction induced by perceived stress.
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8
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Alenezi F, Covington TA, Mukherjee M, Mathai SC, Yu PB, Rajagopal S. Novel Approaches to Imaging the Pulmonary Vasculature and Right Heart. Circ Res 2022; 130:1445-1465. [PMID: 35482838 PMCID: PMC9060389 DOI: 10.1161/circresaha.121.319990] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
There is an increased appreciation for the importance of the right heart and pulmonary circulation in several disease states across the spectrum of pulmonary hypertension and left heart failure. However, assessment of the structure and function of the right heart and pulmonary circulation can be challenging, due to the complex geometry of the right ventricle, comorbid pulmonary airways and parenchymal disease, and the overlap of hemodynamic abnormalities with left heart failure. Several new and evolving imaging modalities interrogate the right heart and pulmonary circulation with greater diagnostic precision. Echocardiographic approaches such as speckle-tracking and 3-dimensional imaging provide detailed assessments of regional systolic and diastolic function and volumetric assessments. Magnetic resonance approaches can provide high-resolution views of cardiac structure/function, tissue characterization, and perfusion through the pulmonary vasculature. Molecular imaging with positron emission tomography allows an assessment of specific pathobiologically relevant targets in the right heart and pulmonary circulation. Machine learning analysis of high-resolution computed tomographic lung scans permits quantitative morphometry of the lung circulation without intravenous contrast. Inhaled magnetic resonance imaging probes, such as hyperpolarized 129Xe magnetic resonance imaging, report on pulmonary gas exchange and pulmonary capillary hemodynamics. These approaches provide important information on right ventricular structure and function along with perfusion through the pulmonary circulation. At this time, the majority of these developing technologies have yet to be clinically validated, with few studies demonstrating the utility of these imaging biomarkers for diagnosis or monitoring disease. These technologies hold promise for earlier diagnosis and noninvasive monitoring of right heart failure and pulmonary hypertension that will aid in preclinical studies, enhance patient selection and provide surrogate end points in clinical trials, and ultimately improve bedside care.
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Affiliation(s)
- Fawaz Alenezi
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC
| | | | | | - Steve C. Mathai
- Johns Hopkins Division of Pulmonary and Critical Care Medicine, Baltimore, MD
| | - Paul B. Yu
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
| | - Sudarshan Rajagopal
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC
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9
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Kita T, Kitamura K. Translational studies of adrenomedullin and related peptides regarding cardiovascular diseases. Hypertens Res 2022; 45:389-400. [PMID: 34992239 PMCID: PMC8732970 DOI: 10.1038/s41440-021-00806-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/24/2021] [Accepted: 10/28/2021] [Indexed: 12/11/2022]
Abstract
Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM levels are markedly increased during severe inflammation, such as that associated with sepsis; thus, AM is expected to be a useful clinical marker and therapeutic agent for inflammation. However, as the increase in AM levels in cardiovascular diseases (CVDs) is relatively low compared to that in infectious diseases, the value of AM as a marker of CVDs seems to be less important. Limitations pertaining to the administrative route and short half-life of AM in the bloodstream (<30 min) restrict the therapeutic applications of AM for CVDs. In early human studies, various applications of AM for CVDs were attempted, including for heart failure, myocardial infarction, pulmonary hypertension, and peripheral artery disease; however, none achieved success. We have developed AM as a therapeutic agent for inflammatory bowel disease in which the vasodilatory effect of AM is minimized. A clinical trial evaluating this AM formulation for acute cerebral infarction is ongoing. We have also developed AM derivatives that exhibit a longer half-life and less vasodilative activity. These AM derivatives can be administered by subcutaneous injection at long-term intervals. Accordingly, these derivatives will reduce the inconvenience in use compared to that for native AM and expand the possible applications of AM for treating CVDs. In this review, we present the latest translational status of AM and its derivatives.
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Affiliation(s)
- Toshihiro Kita
- Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.
| | - Kazuo Kitamura
- Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan
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10
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Holzer P, Holzer-Petsche U. Constipation Caused by Anti-calcitonin Gene-Related Peptide Migraine Therapeutics Explained by Antagonism of Calcitonin Gene-Related Peptide's Motor-Stimulating and Prosecretory Function in the Intestine. Front Physiol 2022; 12:820006. [PMID: 35087426 PMCID: PMC8787053 DOI: 10.3389/fphys.2021.820006] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 12/17/2021] [Indexed: 12/12/2022] Open
Abstract
The development of small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and of monoclonal antibodies targeting the CGRP system has been a major advance in the management of migraine. In the randomized controlled trials before regulatory approval, the safety of these anti-CGRP migraine therapeutics was considered favorable and to stay within the expected profile. Post-approval real-world surveys reveal, however, constipation to be a major adverse event which may affect more than 50% of patients treated with erenumab (an antibody targeting the CGRP receptor), fremanezumab or galcanezumab (antibodies targeting CGRP). In this review article we address the question whether constipation caused by inhibition of CGRP signaling can be mechanistically deduced from the known pharmacological actions and pathophysiological implications of CGRP in the digestive tract. CGRP in the gut is expressed by two distinct neuronal populations: extrinsic primary afferent nerve fibers and distinct neurons of the intrinsic enteric nervous system. In particular, CGRP is a major messenger of enteric sensory neurons which in response to mucosal stimulation activate both ascending excitatory and descending inhibitory neuronal pathways that enable propulsive (peristaltic) motor activity to take place. In addition, CGRP is able to stimulate ion and water secretion into the intestinal lumen. The motor-stimulating and prosecretory actions of CGRP combine in accelerating intestinal transit, an activity profile that has been confirmed by the ability of CGRP to induce diarrhea in mice, dogs and humans. We therefore conclude that the constipation elicited by antibodies targeting CGRP or its receptor results from interference with the physiological function of CGRP in the small and large intestine in which it contributes to the maintenance of peristaltic motor activity, ion and water secretion and intestinal transit.
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Affiliation(s)
- Peter Holzer
- Division of Pharmacology, Otto Loewi Research Centre, Medical University of Graz, Graz, Austria
| | - Ulrike Holzer-Petsche
- Division of Pharmacology, Otto Loewi Research Centre, Medical University of Graz, Graz, Austria
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11
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Chen L, Jung HJ, Datta A, Park E, Poll BG, Kikuchi H, Leo KT, Mehta Y, Lewis S, Khundmiri SJ, Khan S, Chou CL, Raghuram V, Yang CR, Knepper MA. Systems Biology of the Vasopressin V2 Receptor: New Tools for Discovery of Molecular Actions of a GPCR. Annu Rev Pharmacol Toxicol 2022; 62:595-616. [PMID: 34579536 PMCID: PMC10676752 DOI: 10.1146/annurev-pharmtox-052120-011012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Systems biology can be defined as the study of a biological process in which all of the relevant components are investigated together in parallel to discover the mechanism. Although the approach is not new, it has come to the forefront as a result of genome sequencing projects completed in the first few years of the current century. It has elements of large-scale data acquisition (chiefly next-generation sequencing-based methods and protein mass spectrometry) and large-scale data analysis (big data integration and Bayesian modeling). Here we discuss these methodologies and show how they can be applied to understand the downstream effects of GPCR signaling, specifically looking at how the neurohypophyseal peptide hormone vasopressin, working through the V2 receptor and PKA activation, regulates the water channel aquaporin-2. The emerging picture provides a detailedframework for understanding the molecular mechanisms involved in water balance disorders, pointing the way to improved treatment of both polyuric disorders and water-retention disorders causing dilutional hyponatremia.
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Affiliation(s)
- Lihe Chen
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Hyun Jun Jung
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
| | - Arnab Datta
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
- Yenepoya Research Center, Yenepoya, Mangalore 575018, Karnataka, India
| | - Euijung Park
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Brian G Poll
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Hiroaki Kikuchi
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Kirby T Leo
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Yash Mehta
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Spencer Lewis
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Syed J Khundmiri
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Shaza Khan
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Chung-Lin Chou
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Viswanathan Raghuram
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Chin-Rang Yang
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
| | - Mark A Knepper
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
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Shrestha AK, Menon RT, Yallampalli C, Barrios R, Shivanna B. Adrenomedullin Deficiency Potentiates Lipopolysaccharide-Induced Experimental Bronchopulmonary Dysplasia in Neonatal Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:2080-2090. [PMID: 34508690 DOI: 10.1016/j.ajpath.2021.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 08/24/2021] [Accepted: 09/02/2021] [Indexed: 01/12/2023]
Abstract
Lung inflammation interrupts alveolarization and causes bronchopulmonary dysplasia (BPD). Besides mechanical ventilation and hyperoxia, sepsis contributes to BPD pathogenesis. Adrenomedullin (Adm) is a multifunctional peptide that exerts anti-inflammatory effects in the lungs of adult rodents. Whether Adm mitigates sepsis-induced neonatal lung injury is unknown. The lung phenotype of mice exposed to early postnatal lipopolysaccharide (LPS) was recently shown to be similar to that in human BPD. This model was used to test the hypothesis that Adm-deficient neonatal mice will display increased LPS-induced lung injury than their wild-type (WT) littermates. Adm-deficient mice or their WT littermates were intraperitoneally administered 6 mg/kg of LPS or vehicle daily on postnatal days (PNDs) 3 to 5. The lungs were harvested at several time points to quantify inflammation, alveolarization, and vascularization. The extent of LPS-induced lung inflammation in Adm-deficient mice was 1.6-fold to 10-fold higher than their WT littermates. Strikingly, Adm deficiency induced STAT1 activation and potentiated STAT3 activation in LPS-exposed lungs. The severity of LPS-induced interruption of lung development was also greater in Adm-deficient mice at PND7. At PND14, LPS-exposed WT littermates displayed substantial improvement in lung development, whereas LPS-exposed Adm-deficient mice continued to have decreased lung development. These data indicate that Adm is necessary to decrease lung inflammation and injury and promote repair of the injured lungs in LPS-exposed neonatal mice.
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Affiliation(s)
- Amrit K Shrestha
- Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Renuka T Menon
- Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Chandrasekhar Yallampalli
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | - Roberto Barrios
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas
| | - Binoy Shivanna
- Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
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Marichal-Cancino BA, González-Hernández A, Guerrero-Alba R, Medina-Santillán R, Villalón CM. A critical review of the neurovascular nature of migraine and the main mechanisms of action of prophylactic antimigraine medications. Expert Rev Neurother 2021; 21:1035-1050. [PMID: 34388955 DOI: 10.1080/14737175.2021.1968835] [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: 10/20/2022]
Abstract
INTRODUCTION Migraine involves neurovascular, functional, and anatomical alterations. Migraineurs experience an intense unilateral and pulsatile headache frequently accompanied with vomiting, nausea, photophobia, etc. Although there is no ideal preventive medication, frequency in migraine days may be partially decreased by some prophylactics, including antihypertensives, antidepressants, antiepileptics, and CGRPergic inhibitors. However, the mechanisms of action involved in antimigraine prophylaxis remain elusive. AREAS COVERED This review recaps some of the main neurovascular phenomena related to migraine and currently available preventive medications. Moreover, it discusses the major mechanisms of action of the recommended prophylactic medications. EXPERT OPINION In the last three years, migraine prophylaxis has evolved from nonspecific to specific antimigraine treatments. Overall, nonspecific treatments mainly involve neural actions, whereas specific pharmacotherapy (represented by CGRP receptor antagonists and CGRPergic monoclonal antibodies) is predominantly mediated by neurovascular mechanisms that may include, among others: (i) reduction in the cortical spreading depression (CSD)-associated events; (ii) inhibition of pain sensitization; (iii) blockade of neurogenic inflammation; and/or (iv) increase in cranial vascular tone. Accordingly, the novel antimigraine prophylaxis promises to be more effective, devoid of significant adverse effects (unlike nonspecific treatments), and more beneficial for the quality of life of migraineurs.
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Affiliation(s)
- Bruno A Marichal-Cancino
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Ags, México
| | | | - Raquel Guerrero-Alba
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Ags, México
| | - Roberto Medina-Santillán
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina IPN, Ciudad de México C.P, México
| | - Carlos M Villalón
- Departamento de Farmacobiología, Cinvestav-Coapa, Ciudad de México, México
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Harel F, Nguyen QT, Nsaibia MJ, Finnerty V, Morgan A, Sirois M, Villeneuve L, Calderone A, Bergeron A, Brochiero E, Tardif JC, Shi Y, Dupuis J. SPECT imaging of pulmonary vascular disease in bleomycin-induced lung fibrosis using a vascular endothelium tracer. Respir Res 2021; 22:240. [PMID: 34481508 PMCID: PMC8418741 DOI: 10.1186/s12931-021-01836-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 08/31/2021] [Indexed: 11/17/2022] Open
Abstract
Background Pulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is associated to worse outcome. There is a great need for a non-invasive diagnostic modality to detect and evaluate the severity of pulmonary vascular disease (PVD). 99mTc-PulmoBind is a novel imaging agent that binds to the adrenomedullin (AM) receptor on the pulmonary microvascular endothelium. SPECT imaging employing the endothelial cell tracer 99mTc-PulmoBind was used to assess PVD associated with lung fibrosis. Methods Rats with selective right lung bleomycin-induced fibrosis were compared to control rats. SPECT imaging was performed after three weeks with 99mTc-PulmoBind and 99mTc-macroaggregates of albumin (MAA). PH and right ventricular (RV) function were assessed by echocardiography. Lung perfusion was evaluated by fluorescent microangiography. Lung AM receptor expression was measured by qPCR and by immunohistology. Relevance to human IPF was explored by measuring AM receptor expression in lung biopsies from IPF patients and healthy controls. Results The bleomycin group developed preferential right lung fibrosis with remodeling and reduced perfusion as assessed with fluorescent microangiography. These rats developed PH with RV hypertrophy and dysfunction. 99mTc-PulmoBind uptake was selectively reduced by 50% in the right lung and associated with reduced AM receptor expression, PH and RV hypertrophy. AM receptor was co-expressed with the endothelial cell protein CD31 in alveolar capillaries, and markedly reduced after bleomycin. Quantitative dynamic analysis of 99mTc-PulmoBind uptake in comparison to 99mTc-MAA revealed that the latter distributed only according to flow, with about 60% increased left lung uptake while left lung uptake of 99mTc-PulmoBind was not affected. Lung from human IPF patients showed important reduction in AM receptor expression closely associated with CD31. Conclusions SPECT imaging with 99mTc-PulmoBind detects PVD and its severity in bleomycin-induced lung fibrosis. Reduced AM receptor expression in human IPF supports further clinical development of this imaging approach. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-021-01836-3.
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Affiliation(s)
- François Harel
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada.,Department of Radiology, Radio-Oncology and Nuclear Medicine, Faculty of Medicine, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montreal, QC, H3T 1J4, Canada
| | - Quang T Nguyen
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada
| | - Mohamed J Nsaibia
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada
| | - Vincent Finnerty
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada
| | - Arielle Morgan
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada
| | - Martin Sirois
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada.,Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montreal, QC, H3T 1J4, Canada
| | - Louis Villeneuve
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada
| | - Angelino Calderone
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada.,Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montreal, QC, H3T 1J4, Canada
| | - Alexandre Bergeron
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada
| | - Emmanuelle Brochiero
- Department of Medicine, Faculty of Medicine, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montreal, QC, H3T 1J4, Canada.,Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint-Denis Street, Montreal, QC, H2X 0A9, Canada
| | - Jean-Claude Tardif
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada.,Department of Medicine, Faculty of Medicine, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montreal, QC, H3T 1J4, Canada
| | - YanFen Shi
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada
| | - Jocelyn Dupuis
- Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada. .,Department of Medicine, Faculty of Medicine, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montreal, QC, H3T 1J4, Canada.
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Meßlinger K. [Pathophysiological role of calcitonin gene-related peptide (CGRP) in migraine and cluster headache]. Schmerz 2020; 34:181-187. [PMID: 32103345 DOI: 10.1007/s00482-020-00448-y] [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] [Indexed: 01/15/2023]
Abstract
Calcitonin gene-related peptide (CGRP) is released from trigeminal afferents during migraine and cluster headache attacks and can be detected in the jugular plasma. Infusion of CGRP can induce headache attacks in migraine and cluster patients. Inhibition of the CGRP signal system is therapeutic in migraine and cluster headache. CGRP is a potent dilator of intracranial arteries but does not immediately activate the trigeminal pain system. CGRP may act as a signal molecule between different cells in the trigeminal ganglion and enhances nociceptive transmission in the spinal trigeminal nucleus. Peripheral inhibition of the CGRP system reduces these actions. Outside the trigeminovascular system, CGRP is important for maintaining the perfusion of organs in critical situations, promotes growth and repair functions and is an immunomodulatory factor. These actions should be considered when the CGRP system is suppressed for a long time.
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Affiliation(s)
- Karl Meßlinger
- Institut für Physiologie und Pathophysiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstraße 17, 91054, Erlangen, Deutschland.
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Sohn I, Sheykhzade M, Edvinsson L, Sams A. The effects of CGRP in vascular tissue - Classical vasodilation, shadowed effects and systemic dilemmas. Eur J Pharmacol 2020; 881:173205. [PMID: 32442540 DOI: 10.1016/j.ejphar.2020.173205] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/29/2020] [Accepted: 05/14/2020] [Indexed: 02/02/2023]
Abstract
Vascular tissue consists of endothelial cells, vasoactive smooth muscle cells and perivascular nerves. The perivascular sensory neuropeptide CGRP has demonstrated potent vasodilatory effects in any arterial vasculature examined so far, and a local protective CGRP-circuit of sensory nerve terminal CGRP release and smooth muscle cell CGRP action is evident. The significant vasodilatory effect has shadowed multiple other effects of CGRP in the vascular tissue and we therefore thoroughly review vascular actions of CGRP on endothelial cells, vascular smooth muscle cells and perivascular nerve terminals. The actions beyond vasodilation includes neuronal re-uptake and neuromodulation, angiogenic, proliferative and antiproliferative, pro- and anti-inflammatory actions which vary depending on the target cell and anatomical location. In addition to the classical perivascular nerve-smooth muscle CGRP circuit, we review existing evidence for a shadowed endothelial autocrine pathway for CGRP. Finally, we discuss the impact of local and systemic actions of CGRP in vascular regulation and protection from hypertensive and ischemic heart conditions with special focus on therapeutic CGRP agonists and antagonists.
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Affiliation(s)
- Iben Sohn
- Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet Glostrup, Nordstjernevej 42, DK-2600, Glostrup, Denmark
| | - Majid Sheykhzade
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Oe, Denmark
| | - Lars Edvinsson
- Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet Glostrup, Nordstjernevej 42, DK-2600, Glostrup, Denmark; Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden
| | - Anette Sams
- Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet Glostrup, Nordstjernevej 42, DK-2600, Glostrup, Denmark.
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17
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Holmes D, Corr M, Thomas G, Harbinson M, Campbell M, Spiers P, Bell D. Protective effects of intermedin/adrenomedullin-2 in a cellular model of human pulmonary arterial hypertension. Peptides 2020; 126:170267. [PMID: 32017948 DOI: 10.1016/j.peptides.2020.170267] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 01/30/2020] [Accepted: 01/31/2020] [Indexed: 11/18/2022]
Abstract
Proliferation of pulmonary fibroblasts (PF) and distal migration of smooth muscle cells (PSM) are hallmarks of pulmonary arterial hypertension (PAH). Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the Calcitonin Gene-Related Peptide (CGRP)/Adrenomedullin (AM) superfamily. These peptides act via Calcitonin-Like Receptors (CLR) combined with one of three Receptor activity-modifying proteins (RAMPs). IMD/AM2 is a potent pulmonary vasodilator in animal studies. The aim was to describe expression of IMD/AM2, AM and receptor components in human pulmonary vascular cells and to elucidate effects of IMD/AM2 on human PSM migration and PF proliferation. Gene expression was detected by immunofluorescence, immunoblotting and qRT-PCR. Normotension and hypertension were simulated by applying pulsatile mechanical stretch (Flexcell® apparatus). Viable cell numbers were determined by dye exclusion. PSM chemotaxis was measured via Dunn chamber. IMD/AM2 protein was co-expressed with AM and their receptor components in pulmonary artery and microvascular endothelial (PAEC, PMVEC) and non-endothelial cells (PF, PSM), and localised to vesicles. IMD/AM2 was secreted under basal conditions, most abundantly from PF and PMVEC. Secretion from PF and PSM was enhanced by stretch. IMD/AM2 mRNA expression increased in response to hypertensive stretch of PSM. IMD/AM2 inhibited PDGF (10-7 M)-mediated PSM migration maximally at 3 × 10-10 M and PF proliferation maximally at 3 × 10-9 M. Angiotensin II (5 × 10-8 M), normotensive and hypertensive stretch augmented PF proliferation. IMD/AM2 (10-9 M) abolished the proliferative effects of Angiotensin II and normotensive stretch and attenuated the proliferative effect of hypertensive stretch alone and combined with angiotensin II. These findings indicate an important counter-regulatory role for IMD/AM2 in PAH.
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Affiliation(s)
- David Holmes
- School of Medicine, Dentistry and Biomedical Sciences, The Queen's University of Belfast, Northern Ireland, United Kingdom
| | - Michael Corr
- School of Medicine, Dentistry and Biomedical Sciences, The Queen's University of Belfast, Northern Ireland, United Kingdom
| | - Gavin Thomas
- School of Medicine, Dentistry and Biomedical Sciences, The Queen's University of Belfast, Northern Ireland, United Kingdom
| | - Mark Harbinson
- School of Medicine, Dentistry and Biomedical Sciences, The Queen's University of Belfast, Northern Ireland, United Kingdom
| | - Malcolm Campbell
- School of Medicine, Dentistry and Biomedical Sciences, The Queen's University of Belfast, Northern Ireland, United Kingdom
| | - Paul Spiers
- School of Medicine, Dentistry and Biomedical Sciences, The Queen's University of Belfast, Northern Ireland, United Kingdom
| | - David Bell
- School of Medicine, Dentistry and Biomedical Sciences, The Queen's University of Belfast, Northern Ireland, United Kingdom.
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Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache. Brain Sci 2020; 10:brainsci10010030. [PMID: 31935868 PMCID: PMC7016902 DOI: 10.3390/brainsci10010030] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 12/28/2019] [Accepted: 12/30/2019] [Indexed: 02/06/2023] Open
Abstract
Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.
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19
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Borkum JM. CGRP and Brain Functioning: Cautions for Migraine Treatment. Headache 2019; 59:1339-1357. [DOI: 10.1111/head.13591] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Jonathan M. Borkum
- Department of Psychology University of Maine Orono ME USA
- Health Psych Maine Waterville ME USA
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PulmoBind Imaging Measures Reduction of Vascular Adrenomedullin Receptor Activity with Lack of effect of Sildenafil in Pulmonary Hypertension. Sci Rep 2019; 9:6609. [PMID: 31036871 PMCID: PMC6488585 DOI: 10.1038/s41598-019-43225-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 04/16/2019] [Indexed: 01/24/2023] Open
Abstract
Endothelial dysfunction is a core pathophysiologic process in pulmonary arterial hypertension (PAH). We developed PulmoBind (PB), a novel imaging biomarker of the pulmonary vascular endothelium. 99mTechnetium (99mTc)-labelled PB binds to adrenomedullin receptors (AM1) densely expressed in the endothelium of alveolar capillaries. We evaluated the effect of sildenafil on AM1 receptors activity using 99mTc-PB. PAH was induced in rats using the Sugen/hypoxia model and after 3 weeks, animals were allocated to sildenafil (25 or 100 mg/kg/day) for 4 weeks. 99mTc-PB uptake kinetics was assessed by single-photon emission computed tomography. PAH caused right ventricular (RV) hypertrophy that was decreased by low and high sildenafil doses. Sildenafil low and high dose also improved RV function measured from the tricuspid annulus plane systolic excursion. Mean integrated pulmonary uptake of 99mTc-PB was reduced in PAH (508% · min ± 37, p < 0.05) compared to controls (630% · min ± 30), but unchanged by sildenafil at low and high doses. Lung tissue expressions of the AM1 receptor components were reduced in PAH and also unaffected by sildenafil. In experimental angio-proliferative PAH, sildenafil improves RV dysfunction and remodeling, but does not modify pulmonary vascular endothelium dysfunction assessed by the adrenomedullin receptor ligand 99mTc-PB.
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21
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Morikawa S, Iribar H, Gutiérrez-Rivera A, Ezaki T, Izeta A. Pericytes in Cutaneous Wound Healing. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1147:1-63. [DOI: 10.1007/978-3-030-16908-4_1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Alonso Martinez LM, Harel F, Nguyen QT, Létourneau M, D'Oliviera-Sousa C, Meloche B, Finnerty V, Fournier A, Dupuis J, DaSilva JN. Al[ 18F]F-complexation of DFH17, a NOTA-conjugated adrenomedullin analog, for PET imaging of pulmonary circulation. Nucl Med Biol 2018; 67:36-42. [PMID: 30388434 DOI: 10.1016/j.nucmedbio.2018.10.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/01/2018] [Accepted: 10/11/2018] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Adrenomedullin receptors are highly expressed in human alveolar capillaries and provide a molecular target for imaging the integrity of pulmonary microcirculation. In this work, we aimed to develop a NOTA-derivatized adrenomedullin analog (DFH17), radiolabeled with [18F]AlF, for PET imaging of pulmonary microcirculation. METHODS Highly concentrated [18F](AlF)2+ (15 μL) was produced from purified fluorine-18 in NaCl 0.9%. Various complexation experiments were carried out at Al-to-NOTA molar ratios ranging from 1:1 to 1:40 to assess optimal radiolabeling conditions before using the peptide. DFH17 peptide (2 mM, pH 4) was radiolabeled with [18F](AlF)2+ for 15 min at 100 °C in a total volume of 60 μL. As part of the radiolabeling process, parameters such as fluorine-18 activity (~37 and 1480 MBq), concentration of AlCl3 (0.75, 2, 3, 6 or 10 mM) and the effects of hydrophilic organic solvent (aqueous vs ethanol 50%) were studied. The final formulation was tested for purity, identity and stability in saline. Initial in vivo evaluation of [18F]AlF-DFH17 was performed in normal rats by PET/CT. RESULTS The scaled-up production of [18F]AlF-DFH17 was performed in high radiochemical and chemical purities in an overall radiochemical yield of 22-38% (at end-of-synthesis) within 60 min. The final formulation was stable in saline at different radioactive concentrations for 8 h. PET evaluation in rats revealed high lung-to-background ratios and no defluorination in vivo up to 1 h post-injection. CONCLUSION The novel radioconjugate [18F]AlF-DFH17 appears to be a promising PET ligand for pulmonary microcirculation imaging.
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Affiliation(s)
- Luis Michel Alonso Martinez
- University of Montreal Hospital Research Centre, 900 rue Saint-Denis, Montréal, Québec H2X 3H8, Canada; Department of Biomedical Engineering, Faculty of Medicine, Université de Montréal, Pavillon Paul-G. Desmarais, 2960 chemin de la Tour, Montréal, Québec H3T 1J4, Canada; Research Center of the Montreal Heart Institute, 5000 Rue Bélanger, Montréal, Québec H1T 1C8, Canada
| | - François Harel
- Department of Biomedical Engineering, Faculty of Medicine, Université de Montréal, Pavillon Paul-G. Desmarais, 2960 chemin de la Tour, Montréal, Québec H3T 1J4, Canada; Research Center of the Montreal Heart Institute, 5000 Rue Bélanger, Montréal, Québec H1T 1C8, Canada; Department of Radiology, Radio-oncology and Nuclear Medicine, Université de Montréal, Pavillon Roger-Gaudry, 2900 Boulevard Edouard Montpetit, Montréal, Québec H3T 1J4, Canada
| | - Quang T Nguyen
- Research Center of the Montreal Heart Institute, 5000 Rue Bélanger, Montréal, Québec H1T 1C8, Canada
| | - Myriam Létourneau
- Laboratoire D'études Moléculaires et Pharmacologiques des Peptides, INRS-Institut Armand-Frappier, 531 boulevard des Prairies, Laval, Québec H7V 1B7, Canada
| | - Caroline D'Oliviera-Sousa
- Research Center of the Montreal Heart Institute, 5000 Rue Bélanger, Montréal, Québec H1T 1C8, Canada
| | - Bernard Meloche
- Research Center of the Montreal Heart Institute, 5000 Rue Bélanger, Montréal, Québec H1T 1C8, Canada
| | - Vincent Finnerty
- Research Center of the Montreal Heart Institute, 5000 Rue Bélanger, Montréal, Québec H1T 1C8, Canada
| | - Alain Fournier
- Department of Radiology, Radio-oncology and Nuclear Medicine, Université de Montréal, Pavillon Roger-Gaudry, 2900 Boulevard Edouard Montpetit, Montréal, Québec H3T 1J4, Canada
| | - Jocelyn Dupuis
- Research Center of the Montreal Heart Institute, 5000 Rue Bélanger, Montréal, Québec H1T 1C8, Canada; Department of Medicine, Université de Montréal, 2900 boulevard Edouard Montpetit, Montréal, Québec H3T 1J4, Canada
| | - Jean N DaSilva
- University of Montreal Hospital Research Centre, 900 rue Saint-Denis, Montréal, Québec H2X 3H8, Canada; Department of Biomedical Engineering, Faculty of Medicine, Université de Montréal, Pavillon Paul-G. Desmarais, 2960 chemin de la Tour, Montréal, Québec H3T 1J4, Canada; Department of Radiology, Radio-oncology and Nuclear Medicine, Université de Montréal, Pavillon Roger-Gaudry, 2900 Boulevard Edouard Montpetit, Montréal, Québec H3T 1J4, Canada.
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Lo CCW, Moosavi SM, Bubb KJ. The Regulation of Pulmonary Vascular Tone by Neuropeptides and the Implications for Pulmonary Hypertension. Front Physiol 2018; 9:1167. [PMID: 30190678 PMCID: PMC6116211 DOI: 10.3389/fphys.2018.01167] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 08/03/2018] [Indexed: 12/20/2022] Open
Abstract
Pulmonary hypertension (PH) is an incurable, chronic disease of small pulmonary vessels. Progressive remodeling of the pulmonary vasculature results in increased pulmonary vascular resistance (PVR). This causes secondary right heart failure. PVR is tightly regulated by a range of pulmonary vasodilators and constrictors. Endothelium-derived substances form the basis of most current PH treatments. This is particularly the case for pulmonary arterial hypertension. The major limitation of current treatments is their inability to reverse morphological changes. Thus, there is an unmet need for novel therapies to reduce the morbidity and mortality in PH. Microvessels in the lungs are highly innervated by sensory C fibers. Substance P and calcitonin gene-related peptide (CGRP) are released from C-fiber nerve endings. These neuropeptides can directly regulate vascular tone. Substance P tends to act as a vasoconstrictor in the pulmonary circulation and it increases in the lungs during experimental PH. The receptor for substance P, neurokinin 1 (NK1R), mediates increased pulmonary pressure. Deactivation of NK1R with antagonists, or depletion of substance P prevents PH development. CGRP is a potent pulmonary vasodilator. CGRP receptor antagonists cause elevated pulmonary pressure. Thus, the balance of these peptides is crucial within the pulmonary circulation (Graphical Abstract). Limited progress has been made in understanding their impact on pulmonary pathophysiology. This is an intriguing area of investigation to pursue. It may lead to promising new candidate therapies to combat this fatal disease. This review provides a summary of the current knowledge in this area. It also explores possible future directions for neuropeptides in PH.
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Affiliation(s)
- Charmaine C. W. Lo
- Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia
| | - Seyed M. Moosavi
- Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia
- School of Life Sciences, University of Technology Sydney, Ultimo, NSW, Australia
| | - Kristen J. Bubb
- Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia
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Newman JH, Rich S, Abman SH, Alexander JH, Barnard J, Beck GJ, Benza RL, Bull TM, Chan SY, Chun HJ, Doogan D, Dupuis J, Erzurum SC, Frantz RP, Geraci M, Gillies H, Gladwin M, Gray MP, Hemnes AR, Herbst RS, Hernandez AF, Hill NS, Horn EM, Hunter K, Jing ZC, Johns R, Kaul S, Kawut SM, Lahm T, Leopold JA, Lewis GD, Mathai SC, McLaughlin VV, Michelakis ED, Nathan SD, Nichols W, Page G, Rabinovitch M, Rich J, Rischard F, Rounds S, Shah SJ, Tapson VF, Lowy N, Stockbridge N, Weinmann G, Xiao L. Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop Report. Am J Respir Crit Care Med 2017; 195:1661-1670. [PMID: 28430547 PMCID: PMC5476915 DOI: 10.1164/rccm.201701-0150ws] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/18/2017] [Indexed: 12/18/2022] Open
Abstract
The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched "Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics" (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.
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Affiliation(s)
- John H. Newman
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt Medical Center, Nashville, Tennessee
| | - Stuart Rich
- Division of Cardiology, Department of Medicine, Northwestern University, Chicago, Illinois
| | - Steven H. Abman
- Pediatric Heart and Lung Center, University of Colorado, Aurora, Colorado
| | | | | | | | - Raymond L. Benza
- Department of Cardiovascular Disease, Allegheny Health Network, Pittsburgh, Pennsylvania
| | - Todd M. Bull
- Division of Pulmonary and Critical Care Medicine and
| | - Stephen Y. Chan
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | | | - Jocelyn Dupuis
- Department of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Serpil C. Erzurum
- Department of Pathobiology, and
- Department of Medicine, Cleveland Clinic, Cleveland, Ohio
| | | | - Mark Geraci
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Hunter Gillies
- Independent Consultant and Pharmaceutical Physician, Half Moon Bay, California
| | - Mark Gladwin
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Anna R. Hemnes
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt Medical Center, Nashville, Tennessee
| | - Roy S. Herbst
- Division of Medical Oncology, Department of Medicine, Yale University, New Haven, Connecticut
| | | | - Nicholas S. Hill
- Division of Pulmonary, Critical Care, and Sleep Medicine, Tufts University, Boston, Massachusetts
| | - Evelyn M. Horn
- Division of Cardiology, Cornell University, New York, New York
| | - Kendall Hunter
- College of Engineering and Applied Science, University of Colorado, Denver, Colorado
| | - Zhi-Cheng Jing
- FuWai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Roger Johns
- Department of Anesthesiology and Critical Care and
| | | | - Steven M. Kawut
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Tim Lahm
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Jane A. Leopold
- Division of Cardiology, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Greg D. Lewis
- Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts
| | - Stephen C. Mathai
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Vallerie V. McLaughlin
- Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor, Michigan
| | | | - Steven D. Nathan
- Advanced Lung Disease Program, Inova Fairfax Hospital, Falls Church, Virginia
| | - William Nichols
- Department of Human Genetics, Cincinnati Children’s Hospital, Cincinnati, Ohio
| | | | - Marlene Rabinovitch
- Division of Pediatric Cardiology, Department of Pediatrics, Stanford University, Stanford, California
| | - Jonathan Rich
- Division of Cardiology, Department of Medicine, Northwestern University, Chicago, Illinois
| | - Franz Rischard
- Division of Cardiology, University of Arizona, Tucson, Arizona
| | - Sharon Rounds
- Department of Medicine and Laboratory Medicine, Brown University, Providence, Rhode Island
| | - Sanjiv J. Shah
- Division of Cardiology, Department of Medicine, Northwestern University, Chicago, Illinois
| | - Victor F. Tapson
- Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Naomi Lowy
- Division of Cardiovascular and Renal Products, Food and Drug Administration, Office of Drug Evaluation I, Office of New Drugs, Food and Drug Administration Silver Spring, Maryland; and
| | - Norman Stockbridge
- Division of Cardiovascular and Renal Products, Food and Drug Administration, Office of Drug Evaluation I, Office of New Drugs, Food and Drug Administration Silver Spring, Maryland; and
| | - Gail Weinmann
- Division of Lung Diseases, NHLBI, National Institutes of Health, Bethesda, Maryland
| | - Lei Xiao
- Division of Lung Diseases, NHLBI, National Institutes of Health, Bethesda, Maryland
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Xu B, Xu H, Cao H, Liu X, Qin C, Zhao Y, Han X, Li H. Intermedin improves cardiac function and sympathetic neural remodeling in a rat model of post myocardial infarction heart failure. Mol Med Rep 2017. [PMID: 28627670 PMCID: PMC5562092 DOI: 10.3892/mmr.2017.6776] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Emerging evidence has suggested that intermedin (IMD), a novel member of the calcitonin gene-related peptide (CGRP) family, has a wide range of cardioprotective effects. The present study investigated the effects of long-term administration of IMD on cardiac function and sympathetic neural remodeling in heart failure (HF) rats, and studied potential underlying mechanism. HF was induced in rats by myocardial infarction (MI). Male Sprague Dawley rats were randomly assigned to either saline or IMD (0.6 µg/kg/h) treatment groups for 4 weeks post-MI. Another group of sham-operated rats served as controls. Cardiac function was assessed by echocardiography, cardiac catheterization and plasma level of B-type natriuretic peptide (BNP). Cardiac sympathetic neural remodeling was assessed by immunohistochemistical study of tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) immunoreactive nerve fibers. The protein expression levels of nerve growth factor (NGF), TH and GAP43 in the ventricular myocardium were studied by western blotting. Ventricular fibrillation threshold (VFT) was determined to evaluate the incidence of ventricular arrhythmia. Oxidative stress was assessed by detecting the activity of superoxide dismutase and the level of malondialdehyde. Compared with rats administrated with saline, IMD significantly improved cardiac function, decreased the plasma BNP level, attenuated sympathetic neural remodeling, increased VFT and suppressed oxidative stress. In conclusion, these results indicated that IMD prevents ventricle remodeling and improves the performance of a failing heart. In addition, IMD attenuated sympathetic neural remodeling and reduced the incidence of ventricular arrhythmia, which may contribute to its anti-oxidative property. These results implicate IMD as a potential therapeutic agent for the treatment of HF.
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Affiliation(s)
- Bin Xu
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Hao Xu
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Heng Cao
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Xiaoxiao Liu
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Chunhuan Qin
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Yanzhou Zhao
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Xiaolin Han
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Hongli Li
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
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Menon RT, Shrestha AK, Shivanna B. Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants. Biochem Biophys Res Commun 2017; 487:666-671. [PMID: 28438602 DOI: 10.1016/j.bbrc.2017.04.112] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 04/20/2017] [Indexed: 11/25/2022]
Abstract
Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of human infants that is characterized by disrupted lung angiogenesis. Adrenomedullin (AM) is a multifunctional peptide with angiogenic and vasoprotective properties. AM signals via its cognate receptors, calcitonin receptor-like receptor (Calcrl) and receptor activity-modifying protein 2 (RAMP2). Whether hyperoxia affects the pulmonary AM signaling pathway in neonatal mice and whether AM promotes lung angiogenesis in human infants are unknown. Therefore, we tested the following hypotheses: (1) hyperoxia exposure will disrupt AM signaling during the lung development period in neonatal mice; and (2) AM will promote angiogenesis in fetal human pulmonary artery endothelial cells (HPAECs) via extracellular signal-regulated kinases (ERK) 1/2 activation. We initially determined AM, Calcrl, and RAMP2 mRNA levels in mouse lungs on postnatal days (PND) 3, 7, 14, and 28. Next we determined the mRNA expression of these genes in neonatal mice exposed to hyperoxia (70% O2) for up to 14 d. Finally, using HPAECs, we evaluated if AM activates ERK1/2 and promotes tubule formation and cell migration. Lung AM, Calcrl, and RAMP2 mRNA expression increased from PND 3 and peaked at PND 14, a time period during which lung development occurs in mice. Interestingly, hyperoxia exposure blunted this peak expression in neonatal mice. In HPAECs, AM activated ERK1/2 and promoted tubule formation and cell migration. These findings support our hypotheses, emphasizing that AM signaling axis is a potential therapeutic target for human infants with BPD.
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Affiliation(s)
- Renuka T Menon
- Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, United States
| | - Amrit Kumar Shrestha
- Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, United States
| | - Binoy Shivanna
- Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, United States.
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Harel F, Langleben D, Provencher S, Fournier A, Finnerty V, Nguyen QT, Letourneau M, Levac X, Abikhzer G, Guimond J, Mansour A, Guertin MC, Dupuis J. Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial. Eur J Nucl Med Mol Imaging 2017; 44:1136-1144. [PMID: 28236024 PMCID: PMC5434971 DOI: 10.1007/s00259-017-3655-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 02/09/2017] [Indexed: 01/23/2023]
Abstract
PURPOSE The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. METHODS Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. RESULTS PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. CONCLUSIONS In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. CLINICAL TRIAL ClinicalTrials.gov, NCT02216279.
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Affiliation(s)
- François Harel
- Research Center, Montreal Heart Institute, 5000, Belanger Street, Montreal, QC, H1T 1C8, Canada.,Department of Nuclear Medicine, Université de Montréal, Montréal, Québec, Canada
| | - David Langleben
- Lady Davis Institute and Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Steve Provencher
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
| | | | - Vincent Finnerty
- Research Center, Montreal Heart Institute, 5000, Belanger Street, Montreal, QC, H1T 1C8, Canada
| | - Quang T Nguyen
- Research Center, Montreal Heart Institute, 5000, Belanger Street, Montreal, QC, H1T 1C8, Canada
| | | | - Xavier Levac
- Research Center, Montreal Heart Institute, 5000, Belanger Street, Montreal, QC, H1T 1C8, Canada
| | - Gad Abikhzer
- Lady Davis Institute and Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Jean Guimond
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
| | - Asmaa Mansour
- Montreal Health Innovation Coordination Center, Montréal, QC, Canada
| | | | - Jocelyn Dupuis
- Research Center, Montreal Heart Institute, 5000, Belanger Street, Montreal, QC, H1T 1C8, Canada. .,Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
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Heteroreceptors Modulating CGRP Release at Neurovascular Junction: Potential Therapeutic Implications on Some Vascular-Related Diseases. BIOMED RESEARCH INTERNATIONAL 2016; 2016:2056786. [PMID: 28116293 PMCID: PMC5223010 DOI: 10.1155/2016/2056786] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 11/12/2016] [Accepted: 11/27/2016] [Indexed: 01/23/2023]
Abstract
Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide belonging to the calcitonin gene peptide superfamily. CGRP is a potent vasodilator with potential therapeutic usefulness for treating vascular-related disease. This peptide is primarily located on C- and Aδ-fibers, which have extensive perivascular presence and a dual sensory-efferent function. Although CGRP has two major isoforms (α-CGRP and β-CGRP), the α-CGRP is the isoform related to vascular actions. Release of CGRP from afferent perivascular nerve terminals has been shown to result in vasodilatation, an effect mediated by at least one receptor (the CGRP receptor). This receptor is an atypical G-protein coupled receptor (GPCR) composed of three functional proteins: (i) the calcitonin receptor-like receptor (CRLR; a seven-transmembrane protein), (ii) the activity-modifying protein type 1 (RAMP1), and (iii) a receptor component protein (RCP). Although under physiological conditions, CGRP seems not to play an important role in vascular tone regulation, this peptide has been strongly related as a key player in migraine and other vascular-related disorders (e.g., hypertension and preeclampsia). The present review aims at providing an overview on the role of sensory fibers and CGRP release on the modulation of vascular tone.
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Ochoa-Callejero L, Pozo-Rodrigálvarez A, Martínez-Murillo R, Martínez A. Lack of adrenomedullin in mouse endothelial cells results in defective angiogenesis, enhanced vascular permeability, less metastasis, and more brain damage. Sci Rep 2016; 6:33495. [PMID: 27640364 PMCID: PMC5027589 DOI: 10.1038/srep33495] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 08/26/2016] [Indexed: 12/28/2022] Open
Abstract
Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. AM plays critical roles in blood vessels, including regulation of vascular stability and permeability. To elucidate the autocrine/paracrine function of AM in endothelial cells (EC) in vivo, a conditional knockout of AM in EC (AM(EC-KO)) was used. The amount of vascularization of the matrigel implants was lower in AM(EC-KO) mice indicating a defective angiogenesis. Moreover, ablation of AM in EC revealed increased vascular permeability in comparison with wild type (WT) littermates. In addition, AM(EC-KO) lungs exhibited significantly less tumor growth than littermate WT mice using a syngeneic model of metastasis. Furthermore, following middle cerebral artery permanent occlusion, there was a significant infarct size decrease in animals lacking endothelial AM when compared to their WT counterparts. AM is an important regulator of EC function, angiogenesis, tumorigenesis, and brain response to ischemia. Studies of AM should bring novel approaches to the treatment of vascular diseases.
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Affiliation(s)
- Laura Ochoa-Callejero
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), C/Piqueras 98, 26006-Logroño. Spain
| | - Andrea Pozo-Rodrigálvarez
- Neurovascular Research Group, Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Av. Doctor Arce 37, 28002-Madrid. Spain
| | - Ricardo Martínez-Murillo
- Neurovascular Research Group, Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Av. Doctor Arce 37, 28002-Madrid. Spain
| | - Alfredo Martínez
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), C/Piqueras 98, 26006-Logroño. Spain
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Spatial expression of components of a calcitonin receptor-like receptor (CRL) signalling system (CRL, calcitonin gene-related peptide, adrenomedullin, adrenomedullin-2/intermedin) in mouse and human heart valves. Cell Tissue Res 2016; 366:587-599. [DOI: 10.1007/s00441-016-2473-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 07/07/2016] [Indexed: 12/14/2022]
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Yang SI, Yuan Y, Jiao S, Luo QI, Yu J. Calcitonin gene-related peptide protects rats from cerebral ischemia/reperfusion injury via a mechanism of action in the MAPK pathway. Biomed Rep 2016; 4:699-703. [PMID: 27284409 PMCID: PMC4887836 DOI: 10.3892/br.2016.658] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 04/14/2016] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the protective function and underlying mechanism of calcitonin gene-related peptide (CGRP) on cerebral ischemia/reperfusion damage in rats. Adult male Wistar rats were selected for the establishment of an ischemia/reperfusion injury model through the application of a middle cerebral artery occlusion. Animals were randomly divided into 6 groups of 24 animals. Drugs were administered according to the design of each group; animals were administered CGRP, CGRP8-37, PD98059 and SB20358. The neurobehavioral scores of the rat cerebral ischemia model in each group were calculated. The infarction range of the rat brain tissues was observed by 2,3,5-triphenyltetrazolium chloride staining. The expression levels of three proteins, phosphorylated c-Jun N-terminal kinase (JNK)/JNK, phosphorylated extracellular signal-regulated protein kinase (ERK)/ERK and p-p38/p38, in the mitogen-activated protein kinase (MAPK) pathway in the brain tissues was detected by western blotting. The results showed that CGRP could improve the neurobehavioral function of the ischemic rats and reduce the infarction range. Western blotting results confirmed that the function of the CGRP was mediated mainly through the reduction of the JNK and p38 phosphorylation and the promotion of ERK phosphorylation. Therefore, the present study confirmed that an increase in the exogenous CRGP could effectively improve ischemia/reperfusion injury of the brain tissue. The mechanisms of action were achieved through a reduction in JNK and p38 phosphorylation and an increase in ERL phosphorylation in the MAPK pathway. These mechanisms were interdependent.
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Affiliation(s)
- S I Yang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China; Department of Pediatric Neurology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yongjie Yuan
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Shan Jiao
- Department of Endodontics, Stomatological Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Q I Luo
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jinlu Yu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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Bell D, Campbell M, McAleer SF, Ferguson M, Donaghy L, Harbinson MT. Endothelium-derived intermedin/adrenomedullin-2 protects human ventricular cardiomyocytes from ischaemia-reoxygenation injury predominantly via the AM₁ receptor. Peptides 2016; 76:1-13. [PMID: 26743504 DOI: 10.1016/j.peptides.2015.12.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/09/2015] [Accepted: 12/23/2015] [Indexed: 02/07/2023]
Abstract
Application of intermedin/adrenomedullin-2 (IMD/AM-2) protects cultured human cardiac vascular cells and fibroblasts from oxidative stress and simulated ischaemia-reoxygenation injury (I-R), predominantly via adrenomedullin AM1 receptor involvement; similar protection had not been investigated previously in human cardiomyocytes (HCM). Expression of IMD, AM and their receptor components was studied in HCM. Receptor subtype involvement in protection by exogenous IMD against injury by simulated I-R was investigated using receptor component-specific siRNAs. Direct protection by endogenous IMD against HCM injury, both as an autocrine factor produced in HCM themselves and as a paracrine factor released from HCMEC co-cultured with HCM, was investigated using peptide-specific siRNA for IMD. IMD, AM and their receptor components (CLR, RAMPs1-3) were expressed in HCM. IMD 1nmol L(-1), applied either throughout ischaemia (3h) and re-oxygenation (1h) or during re-oxygenation (1h) alone, attenuated HCM injury (P<0.05); cell viabilities were 59% and 61% respectively vs. 39% in absence of IMD. Cytoskeletal disruption, protein carbonyl formation and caspase activity followed similar patterns. Pre-treatment (4 days) of HCM with CLR and RAMP2 siRNAs attenuated (P<0.05) protection by exogenous IMD. Pre-treatment of HCMEC with IMD (and AM) siRNA augmented (P<0.05) I-R injury: cell viabilities were 22% (and 32%) vs. 39% untreated HCMEC. Pre-treatment of HCM with IMD (and AM) siRNA did not augment HCM injury: cell viabilities were 37% (and 39%) vs. 39% untreated HCM. Co-culture with HCMEC conferred protection from injury on HCM; such protection was attenuated when HCMEC were pre-treated with IMD (but not AM) siRNA before co-culture. Although IMD is present in HCM, IMD derived from HCMEC and acting in a paracrine manner, predominantly via AM1 receptors, makes a marked contribution to cardiomyocyte protection by the endogenous peptide against acute I-R injury.
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Affiliation(s)
- David Bell
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, United Kingdom.
| | - Malcolm Campbell
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, United Kingdom
| | - Stephen F McAleer
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, United Kingdom
| | - Matthew Ferguson
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, United Kingdom
| | - Liz Donaghy
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, United Kingdom
| | - Mark T Harbinson
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, United Kingdom
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Yang W, Xv M, Yang WC, Wang N, Zhang XZ, Li WZ. Exogenous α-calcitonin gene-related peptide attenuates lipopolysaccharide-induced acute lung injury in rats. Mol Med Rep 2015; 12:2181-8. [PMID: 25892548 DOI: 10.3892/mmr.2015.3620] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 10/24/2014] [Indexed: 11/06/2022] Open
Abstract
α-Calcitonin gene-related peptide (α-CGRP) is a 37 amino-acid neuropeptide that is primarily released from C-type sensory neurons. α-CGRP exerts multiple modulatory effects on immune responses and visceral organ function, but the role of exogenous α-CGRP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has remained to be elucidated. Forty-eight rats were randomized to receive continuous intraperitoneal infusion of α-CGRP (0.4 μg/kg/min) or normal saline for 30 min, followed by intratracheal injection of 0.5 mg/kg LPS or saline. There were four groups of animals: The saline-saline (S-S) group; the saline-α-CGRP (S-C) group; the LPS-saline (L-S) group and the LPS-α-CGRP (L-C) group. Mean arterial pressure and arterial blood gases were assessed prior to α-CGRP and LPS administration and every hour following LPS treatment. After 4 h, bronchoalveolar lavage was performed and used to assess total cell count and levels of tumor necrosis factor-α, interleukin-1β, intracellular cell adhesion molecule 1 and macrophage inflammatory protein 2. Lung tissue was also collected for assessing wet-to-dry (W/D) ratio, histology and Evans blue (EB) dye extravasation. Pulmonary α-CGRP concentration and α-CGRP receptor expression were also examined, and inducible cyclic adenosine monophosphate early repressor (ICER) and TNF-α mRNA expression levels were measured. Treatment with exogenous α-CGRP improved oxygenation during LPS-induced ALI. Correspondingly, histological injury, total cell count, inflammatory cytokine levels, W/D ratio and EB dye extravasation were also significantly reduced. α-CGRP receptor 1 expression was noted in pulmonary endothelial cells and alveolar macrophages and α-CGRP receptor expression levels were decreased during ALI, whereas pulmonary α-CGRP expression was continuously increased. Furthermore, exogenous α-CGRP induced upregulation of ICER during LPS-induced ALI. In conclusion, exogenous α-CGRP improved oxygenation and ameliorated lung damage in LPS-induced ALI, and these effects were associated with the upregulation of ICER.
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Affiliation(s)
- Wang Yang
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Meng Xv
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Wan Chao Yang
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Nan Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xue Zhong Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Wen Zhi Li
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Harel F, Levac X, Nguyen QT, Létourneau M, Marcil S, Finnerty V, Cossette M, Fournier A, Dupuis J. Molecular imaging of the human pulmonary vascular endothelium using an adrenomedullin receptor ligand. Mol Imaging 2015; 14:7290201500003. [PMID: 25812438 DOI: 10.2310/7290.2015.00003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans (N = 20) were included into escalating groups of 5 mCi (n = 5), 10 mCi (n = 5), or 15 mCi (n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension.
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Dupuis J, Harel F, Nguyen QT. Molecular imaging of the pulmonary circulation in health and disease. Clin Transl Imaging 2014; 2:415-426. [PMID: 25360422 PMCID: PMC4209091 DOI: 10.1007/s40336-014-0076-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 08/15/2014] [Indexed: 11/29/2022]
Abstract
The pulmonary circulation, at the unique crossroads between the left and the right heart, is submitted to large physiologic hemodynamic variations and possesses numerous important metabolic functions mediated through its vast endothelial surface. There are many pathologic conditions that can directly or indirectly affect the pulmonary vasculature and modify its physiology and functions. Pulmonary hypertension, the end result of many of these affections, is unfortunately diagnosed too late in the disease process, meaning that there is a crying need for earlier diagnosis and surrogate markers of disease progression and regression. By targeting endothelial, medial and adventitial targets of the pulmonary vasculature, novel molecular imaging agents could provide early detection of physiologic and biologic perturbation in the pulmonary circulation. This review provides the rationale for the development of molecular imaging agents for the diagnosis and follow-up of disorders of the pulmonary circulation and discusses promising targets for SPECT and positron emission tomographic imaging.
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Affiliation(s)
- Jocelyn Dupuis
- Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC H1T 1C8 Canada ; Department of Medicine, Université de Montréal, Montreal, QC Canada
| | - François Harel
- Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC H1T 1C8 Canada ; Department of Radiology, Radio-Oncology and Nuclear Medicine Université de Montréal, Montreal, QC Canada
| | - Quang T Nguyen
- Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC H1T 1C8 Canada
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Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 2014; 94:1099-142. [PMID: 25287861 PMCID: PMC4187032 DOI: 10.1152/physrev.00034.2013] [Citation(s) in RCA: 851] [Impact Index Per Article: 77.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.
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Affiliation(s)
- F A Russell
- Cardiovascular Division, BHF Centre of Research Excellence & Centre of Integrative Biomedicine, King's College London, Waterloo Campus, London SE1 9NH, United Kingdom
| | - R King
- Cardiovascular Division, BHF Centre of Research Excellence & Centre of Integrative Biomedicine, King's College London, Waterloo Campus, London SE1 9NH, United Kingdom
| | - S-J Smillie
- Cardiovascular Division, BHF Centre of Research Excellence & Centre of Integrative Biomedicine, King's College London, Waterloo Campus, London SE1 9NH, United Kingdom
| | - X Kodji
- Cardiovascular Division, BHF Centre of Research Excellence & Centre of Integrative Biomedicine, King's College London, Waterloo Campus, London SE1 9NH, United Kingdom
| | - S D Brain
- Cardiovascular Division, BHF Centre of Research Excellence & Centre of Integrative Biomedicine, King's College London, Waterloo Campus, London SE1 9NH, United Kingdom
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Nagasaki S, Fukui M, Asano S, Ono K, Miki Y, Araki SI, Isobe M, Nakashima N, Takahashi K, Sasano H, Sato J. Induction of adrenomedullin 2/intermedin expression by thyroid stimulating hormone in thyroid. Mol Cell Endocrinol 2014; 395:32-40. [PMID: 25102228 DOI: 10.1016/j.mce.2014.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 07/09/2014] [Accepted: 07/11/2014] [Indexed: 10/24/2022]
Abstract
TSH is the important regulator of thyroid function but detailed molecular mechanisms have not been clarified. We first generated the iodine deficient (ID) rat in which goiter is induced by accelerated endogenous TSH secretion. The result of microarray analysis demonstrated markedly increased levels of adrenomedullin 2/intermedin (AM2/IMD) expression in the ID rat thyroid. AM2/IMD is a potent vasodilator. AM2/IMD mRNA expression was induced by TSH in a rat thyroid follicular cell line FRTL-5. Immunohistochemical analysis in human normal and Graves' disease thyroid revealed that AM2/IMD immunoreactivity was detected in follicular cells and more pronounced in Graves' disease. These results indicated that TSH induced AM2/IMD expression in the rat thyroid gland and it could locally work as a potent vasodilator, resulting in the expansion of thyroid inter-follicular capillaries. AM2/IMD could also contribute to facilitate thyroid hormone synthesis possibly via vasodilation effects and/or cAMP stimulating effects in the human thyroid gland.
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Affiliation(s)
- Shuji Nagasaki
- Drug Discovery Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan; Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Motoko Fukui
- Safety Research Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
| | - Satoko Asano
- Drug Discovery Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
| | - Katsuhiko Ono
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Miki
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Sei-ichi Araki
- Safety Research Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
| | - Mitsui Isobe
- Safety Research Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
| | - Noriaki Nakashima
- Department of Breast and Endocrine Surgery, Tohoku University Hospital, Sendai, Japan
| | - Kazuhiro Takahashi
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jun Sato
- Drug Discovery Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
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Wong HK, Tang F, Cheung TT, Cheung BMY. Adrenomedullin and diabetes. World J Diabetes 2014; 5:364-371. [PMID: 24936257 PMCID: PMC4058740 DOI: 10.4239/wjd.v5.i3.364] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/19/2013] [Accepted: 05/08/2014] [Indexed: 02/05/2023] Open
Abstract
Adrenomedullin (ADM) is a peptide hormone widely expressed in different tissues, especially in the vasculature. Apart from its vasodilatatory and hypotensive effect, it plays multiple roles in the regulation of hormonal secretion, glucose metabolism and inflammatory response. ADM regulates insulin balance and may participate in the development of diabetes. The plasma level of ADM is increased in people with diabetes, while in healthy individuals the plasma ADM concentration remains low. Plasma ADM levels are further increased in patients with diabetic complications. In type 1 diabetes, plasma ADM level is correlated with renal failure and retinopathy, while in type 2 diabetes its level is linked with a wider range of complications. The elevation of ADM level in diabetes may be due to hyperinsulinemia, oxidative stress and endothelial injury. At the same time, a rise in plasma ADM level can trigger the onset of diabetes. Strategies to reduce ADM level should be explored so as to reduce diabetic complications.
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Hirose T, Totsune K, Mori N, Morimoto R, Hashimoto M, Nakashige Y, Metoki H, Asayama K, Kikuya M, Ohkubo T, Hashimoto J, Sasano H, Kohzuki M, Takahashi K, Imai Y. Increased expression of adrenomedullin 2/intermedin in rat hearts with congestive heart failure. Eur J Heart Fail 2014; 10:840-9. [DOI: 10.1016/j.ejheart.2008.06.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2008] [Revised: 04/29/2008] [Accepted: 06/30/2008] [Indexed: 10/21/2022] Open
Affiliation(s)
- Takuo Hirose
- Department of Clinical Pharmacology and Therapeutics; Tohoku University Graduate School of Pharmaceutical Sciences and Medicine; 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
| | - Kazuhito Totsune
- Department of Clinical Pharmacology and Therapeutics; Tohoku University Graduate School of Pharmaceutical Sciences and Medicine; 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
- Tohoku University 21st Center of Excellence Program “Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation” (CRESCENDO); 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
| | - Nobuyoshi Mori
- Department of Internal Medicine and Rehabilitation Science; Tohoku University School of Medicine; 1-1 Seiryo-machi Aoba-ku Sendai 980-8574 Japan
| | - Ryo Morimoto
- Department of Medicine; Tohoku University School of Medicine; 1-1 Seiryo-machi Aoba-ku Sendai 980-8574 Japan
| | - Masahiro Hashimoto
- Department of Clinical Pharmacology and Therapeutics; Tohoku University Graduate School of Pharmaceutical Sciences and Medicine; 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
| | - Yukiko Nakashige
- Department of Clinical Pharmacology and Therapeutics; Tohoku University Graduate School of Pharmaceutical Sciences and Medicine; 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
| | - Hirohito Metoki
- Department of Clinical Pharmacology and Therapeutics; Tohoku University Graduate School of Pharmaceutical Sciences and Medicine; 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
- Department of Medical Genetics; Tohoku University School of Medicine; 1-1 Seiryo-machi Aoba-ku Sendai 980-8574 Japan
| | - Kei Asayama
- Tohoku University 21st Center of Excellence Program “Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation” (CRESCENDO); 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
| | - Masahiro Kikuya
- Department of Clinical Pharmacology and Therapeutics; Tohoku University Graduate School of Pharmaceutical Sciences and Medicine; 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
| | - Takayoshi Ohkubo
- Tohoku University 21st Center of Excellence Program “Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation” (CRESCENDO); 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
- Department of Planning for Drug Development and Clinical Evaluation; Tohoku University Graduate School of Pharmaceutical Sciences and Medicine; 2-1 Seiryo-machi Aoba-ku Sendai 980-8575 Japan
| | - Junichiro Hashimoto
- Tohoku University 21st Center of Excellence Program “Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation” (CRESCENDO); 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
- Department of Planning for Drug Development and Clinical Evaluation; Tohoku University Graduate School of Pharmaceutical Sciences and Medicine; 2-1 Seiryo-machi Aoba-ku Sendai 980-8575 Japan
| | - Hironobu Sasano
- Department of Pathology; Tohoku University School of Medicine; 1-1 Seiryo-machi Aoba-ku Sendai 980-8574 Japan
| | - Masahiro Kohzuki
- Department of Internal Medicine and Rehabilitation Science; Tohoku University School of Medicine; 1-1 Seiryo-machi Aoba-ku Sendai 980-8574 Japan
| | - Kazuhiro Takahashi
- Tohoku University 21st Center of Excellence Program “Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation” (CRESCENDO); 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
- Department of Endocrinology and Applied Medical Science; Tohoku University Graduate School of Medicine; 2-1 Seiryo-machi Aoba-ku Sendai 980-8575 Japan
| | - Yutaka Imai
- Department of Clinical Pharmacology and Therapeutics; Tohoku University Graduate School of Pharmaceutical Sciences and Medicine; 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
- Tohoku University 21st Center of Excellence Program “Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation” (CRESCENDO); 6-3 Aramaki-aza-aoba Aoba-ku Sendai 980-8578 Japan
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Chéret J, Lebonvallet N, Carré JL, Misery L, Le Gall-Ianotto C. Role of neuropeptides, neurotrophins, and neurohormones in skin wound healing. Wound Repair Regen 2013; 21:772-88. [PMID: 24134750 DOI: 10.1111/wrr.12101] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 07/01/2013] [Indexed: 12/01/2022]
Abstract
Due to the close interactions between the skin and peripheral nervous system, there is increasing evidence that the cutaneous innervation is an important modulator of the normal wound healing process. The communication between sensory neurons and skin cells involves a variety of molecules (neuropeptides, neurohormones, and neurotrophins) and their specific receptors expressed by both neuronal and nonneuronal skin cells. It is well established that neurotransmitters and nerve growth factors released in skin have immunoregulatory roles and can exert mitogenic actions; they could also influence the functions of the different skin cell types during the wound healing process.
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Affiliation(s)
- Jérémy Chéret
- Laboratory of Neurosciences of Brest (EA4685), University of Western Brittany, Brest, France
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Létourneau M, Nguyen QT, Harel F, Fournier A, Dupuis J. PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool. J Nucl Med 2013; 54:1789-96. [DOI: 10.2967/jnumed.112.118984] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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Sugimoto Y, Shiraishi S, Yasuda T, Hamada H, Kawamoto M. Intrathecal adrenomedullin modulates acute inflammatory pain in the rat formalin test. Neurosci Lett 2013; 552:146-50. [PMID: 23939287 DOI: 10.1016/j.neulet.2013.07.055] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 07/25/2013] [Accepted: 07/31/2013] [Indexed: 11/25/2022]
Abstract
Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pronociceptive mediator. This study was undertaken to investigate the role of AM in acute inflammatory pain induced by formalin injection in rats. Interestingly Cerebrospinal fluid (CSF) levels of AM increased 45 min after formalin injection and a selective AM receptor antagonist, AM22-52, administered intrathecally (i.t.) decreased phase 2 flinching in a dose-dependent manner but not phase 1 flinching during the formalin test. This anti-hyperalgesic effect of i.t. AM22-52 lasted for 4 h or more. AM in the CSF contributes to the modulation of acute inflammatory pain in the formalin test, and blocking downstream signaling effects of the AM receptor has the potential to relieve pain associated with acute inflammation.
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Affiliation(s)
- Yuki Sugimoto
- Department of Anesthesiology and Critical Care, Division of Clinical Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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Hagner S, Welz H, Kicic A, Alrifai M, Marsh LM, Sutanto EN, Ling KM, Stick SM, Müller B, Weissmann N, Renz H. Suppression of adrenomedullin contributes to vascular leakage and altered epithelial repair during asthma. Allergy 2012; 67:998-1006. [PMID: 22686590 DOI: 10.1111/j.1398-9995.2012.02851.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2012] [Indexed: 12/25/2022]
Abstract
BACKGROUND The anti-inflammatory peptide, adrenomedullin (AM), and its cognate receptor are expressed in lung tissue, but its pathophysiological significance in airway inflammation is unknown. OBJECTIVES This study investigated whether allergen-induced airway inflammation involves an impaired local AM response. METHODS Airway AM expression was measured in acute and chronically sensitized mice following allergen inhalation and in airway epithelial cells of asthmatic and nonasthmatic patients. The effects of AM on experimental allergen-induced airway inflammation and of AM on lung epithelial repair in vitro were investigated. RESULTS Adrenomedullin mRNA levels were significantly (P < 0.05) reduced in acute ovalbumin (OVA)-sensitized mice after OVA challenge, by over 60% at 24 h and for up to 6 days. Similarly, reduced AM expression was observed in two models of chronic allergen-induced inflammation, OVA- and house dust mite-sensitized mice. The reduced AM expression was restricted to airway epithelial and endothelial cells, while AM expression in alveolar macrophages was unaltered. Intranasal AM completely attenuated the OVA-induced airway hyperresponsiveness and mucosal plasma leakage but had no effect on inflammatory cells or cytokines. The effects of inhaled AM were reversed by pre-inhalation of the putative AM receptor antagonist, AM ((22-52)) . AM mRNA levels were significantly (P < 0.05) lower in human asthmatic airway epithelial samples than in nonasthmatic controls. In vitro, AM dose-dependently (10(-11) -10(-7) M) accelerated experimental wound healing in human and mouse lung epithelial cell monolayers and stimulated epithelial cell migration. CONCLUSION Adrenomedullin suppression in T(H) 2-related inflammation is of pathophysiological significance and represents loss of a factor that maintains tissue integrity during inflammation.
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Affiliation(s)
- S. Hagner
- Institute of Laboratory Medicine; Medical Faculty - Philipps University of Marburg; Biomedical Research Center (BMFZ); Marburg; Germany
| | - H. Welz
- Institute of Laboratory Medicine; Medical Faculty - Philipps University of Marburg; Biomedical Research Center (BMFZ); Marburg; Germany
| | | | - M. Alrifai
- Institute of Laboratory Medicine; Medical Faculty - Philipps University of Marburg; Biomedical Research Center (BMFZ); Marburg; Germany
| | - L. M. Marsh
- Institute of Laboratory Medicine; Medical Faculty - Philipps University of Marburg; Biomedical Research Center (BMFZ); Marburg; Germany
| | | | - K.-M. Ling
- Telethon Institute for Child Health Research; Centre for Health Research; The University of Western Australia; Nedlands; WA; Australia
| | | | - B. Müller
- Laboratory of Respiratory Cell Biology; Department of Internal Medicine; Medical Faculty - Philipps University of Marburg; Marburg; Germany
| | - N. Weissmann
- University of Giessen Lung Center; Giessen; Germany
| | - H. Renz
- Institute of Laboratory Medicine; Medical Faculty - Philipps University of Marburg; Biomedical Research Center (BMFZ); Marburg; Germany
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Cottrell GS, Alemi F, Kirkland JG, Grady EF, Corvera CU, Bhargava A. Localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in human gastrointestinal tract. Peptides 2012; 35:202-11. [PMID: 22484227 PMCID: PMC3356482 DOI: 10.1016/j.peptides.2012.03.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Revised: 03/20/2012] [Accepted: 03/21/2012] [Indexed: 11/28/2022]
Abstract
Calcitonin gene-related peptide (CGRP) exerts its diverse effects on vasodilation, nociception, secretion, and motor function through a heterodimeric receptor comprising of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). Despite the importance of CLR·RAMP1 in human disease, little is known about its distribution in the human gastrointestinal (GI) tract, where it participates in inflammation and pain. In this study, we determined that CLR and RAMP1 mRNAs are expressed in normal human stomach, ileum and colon by RT-PCR. We next characterized antibodies that we generated to rat CLR and RAMP1 in transfected HEK cells. Having characterized these antibodies in vitro, we then localized CLR-, RAMP1-, CGRP- and intermedin-immunoreactivity (IMD-IR) in various human GI segments. In the stomach, nerve bundles in the myenteric plexus and nerve fibers throughout the circular and longitudinal muscle had prominent CLR-IR. In the proximal colon and ileum, CLR was found in nerve varicosities of the myenteric plexus and surrounding submucosal neurons. Interestingly, CGRP expressing fibers did not co-localize, but were in close proximity to CLR. However, CLR and RAMP1, the two subunits of a functional CGRP receptor were clearly localized in myenteric plexus, where they may form functional cell-surface receptors. IMD, another member of calcitonin peptide family was also found in close proximity to CLR, and like CGRP, did not co-localize with either CLR or RAMP1 receptors. Thus, CGRP and IMD appear to be released locally, where they can mediate their effect on their receptors regulating diverse functions such as inflammation, pain and motility.
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Affiliation(s)
- Graeme S. Cottrell
- Department of Surgery, Center for Neurobiology of Digestive Diseases, University of California San Francisco, 521 Parnassus Ave, San Francisco, CA 94143-0660
- Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK
- Co-first authors
| | - Farzad Alemi
- Department of Surgery, Center for Neurobiology of Digestive Diseases, University of California San Francisco, 521 Parnassus Ave, San Francisco, CA 94143-0660
- Co-first authors
| | - Jacob G. Kirkland
- Department of Surgery, Center for Neurobiology of Digestive Diseases, University of California San Francisco, 521 Parnassus Ave, San Francisco, CA 94143-0660
- Co-first authors
| | - Eileen F. Grady
- Department of Surgery, Center for Neurobiology of Digestive Diseases, University of California San Francisco, 521 Parnassus Ave, San Francisco, CA 94143-0660
| | - Carlos U. Corvera
- Department of Surgery, Center for Neurobiology of Digestive Diseases, University of California San Francisco, 521 Parnassus Ave, San Francisco, CA 94143-0660
- Department of Veterans Affairs Medical Center, San Francisco, CA 94143
- Address Correspondence to: Aditi Bhargava, PhD, Department of Surgery, Rm Med Sci 1268, Box 0660, University of California San Francisco, San Francisco, CA 94143, Tel: 1-415-502-8453, Fax: 1-415-476-0936, , Carlos U. Corvera, MD, Veterans Administrative Medical Center, Department of Surgery, Mail code 112, 4150 Clement Street, University of California San Francisco, San Francisco, CA 94121, Tel: 1-415-221-4810 x4581, Fax: 1-415-476-0936,
| | - Aditi Bhargava
- Department of Surgery, Center for Neurobiology of Digestive Diseases, University of California San Francisco, 521 Parnassus Ave, San Francisco, CA 94143-0660
- Address Correspondence to: Aditi Bhargava, PhD, Department of Surgery, Rm Med Sci 1268, Box 0660, University of California San Francisco, San Francisco, CA 94143, Tel: 1-415-502-8453, Fax: 1-415-476-0936, , Carlos U. Corvera, MD, Veterans Administrative Medical Center, Department of Surgery, Mail code 112, 4150 Clement Street, University of California San Francisco, San Francisco, CA 94121, Tel: 1-415-221-4810 x4581, Fax: 1-415-476-0936,
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Bell D, Campbell M, Ferguson M, Sayers L, Donaghy L, O'Regan A, Jewhurst V, Harbinson M. AM₁-receptor-dependent protection by intermedin of human vascular and cardiac non-vascular cells from ischaemia-reperfusion injury. J Physiol 2011; 590:1181-97. [PMID: 22183724 DOI: 10.1113/jphysiol.2011.221895] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Intermedin (IMD) protects rodent heart and vasculature from oxidative stress and ischaemia. Less is known about distribution of IMD and its receptors and the potential for similar protection in man. Expression of IMD and receptor components were studied in human aortic endothelium cells (HAECs), smooth muscle cells (HASMCs), cardiac microvascular endothelium cells (HMVECs) and fibroblasts (v-HCFs). Receptor subtype involvement in protection by IMD against injury by hydrogen peroxide (H₂O₂, 1 mmol l⁻¹) and simulated ischaemia and reperfusion were investigated using receptor component-specific siRNAs. IMD and CRLR, RAMP1, RAMP2 and RAMP3 were expressed in all cell types.When cells were treated with 1 nmol l⁻¹ IMD during exposure to 1 mmol l⁻¹ H₂O₂ for 4 h, viability was greater vs. H2O2 alone (P<0.05 for all cell types). Viabilities under 6 h simulated ischaemia differed (P<0.05) in the absence and presence of 1 nmol l⁻¹ IMD: HAECs 63% and 85%; HMVECs 51% and 68%; v-HCFs 42% and 96%. IMD 1 nmol l⁻¹ present throughout ischaemia (3 h) and reperfusion (1 h) attenuated injury (P<0.05): viabilities were 95%, 74% and 82% for HAECs, HMVECs and v-HCFs, respectively, relative to those in the absence of IMD (62%, 35%, 32%, respectively). When IMD 1 nmol l⁻¹ was present during reperfusion only, protection was still evident (P<0.05, 79%, 55%, 48%, respectively). Cytoskeletal disruption and protein carbonyl formation followed similar patterns. Pre-treatment (4 days) of HAECs with CRLR or RAMP2, but not RAMP1 or RAMP3, siRNAs abolished protection by IMD (1 nmol l⁻¹) against ischaemia-reperfusion injury. IMD protects human vascular and cardiac non-vascular cells from oxidative stress and ischaemia-reperfusion,predominantly via AM1 receptors.
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Affiliation(s)
- David Bell
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, UK.
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Kuwasako K, Kitamura K, Nagata S, Hikosaka T, Takei Y, Kato J. Shared and separate functions of the RAMP-based adrenomedullin receptors. Peptides 2011; 32:1540-50. [PMID: 21645567 DOI: 10.1016/j.peptides.2011.05.022] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2011] [Revised: 05/20/2011] [Accepted: 05/20/2011] [Indexed: 11/25/2022]
Abstract
Adrenomedullin (AM) is a novel hypotensive peptide that exerts a variety of strongly protective effects against multiorgan damage. AM-specific receptors were first identified as heterodimers composed of calcitonin-receptor-like receptor (CLR), a G protein coupled receptor, and one of two receptor activity-modifying proteins (RAMP2 or RAMP3), which are accessory proteins containing a single transmembrane domain. RAMPs are required for the surface delivery of CLR and the determination of its phenotype. CLR/RAMP2 (AM₁ receptor) is more highly AM-specific than CLR/RAMP3 (AM₂ receptor). Although there have been no reports showing differences in intracellular signaling via the two AM receptors, in vitro studies have shed light on their distinct trafficking and functionality. In addition, the tissue distributions of RAMP2 and RAMP3 differ, and their gene expression is differentially altered under pathophysiological conditions, which is suggestive of the separate roles played by AM₁ and AM₂ receptors in vivo. Both AM and the AM₁ receptor, but not the AM₂ receptor, are crucial for the development of the fetal cardiovascular system and are able to effectively protect against various vascular diseases. However, AM₂ receptors reportedly play an important role in maintaining a normal body weight in old age and may be involved in immune function. In this review article, we focus on the shared and separate functions of the AM receptor subtypes and also discuss the potential for related drug discovery. In addition, we mention their possible function as receptors for AM2 (or intermedin), an AM-related peptide whose biological functions are similar to those of AM.
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Affiliation(s)
- Kenji Kuwasako
- Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, Miyazaki 889-1692, Japan.
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Castrop H, Höcherl K, Kurtz A, Schweda F, Todorov V, Wagner C. Physiology of Kidney Renin. Physiol Rev 2010; 90:607-73. [PMID: 20393195 DOI: 10.1152/physrev.00011.2009] [Citation(s) in RCA: 199] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca2+(inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-( 1 – 7 ).
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Affiliation(s)
- Hayo Castrop
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Klaus Höcherl
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Armin Kurtz
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Frank Schweda
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Vladimir Todorov
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Charlotte Wagner
- Institute of Physiology, University of Regensburg, Regensburg, Germany
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Villalón CM, Olesen J. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol Ther 2009; 124:309-23. [DOI: 10.1016/j.pharmthera.2009.09.003] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2009] [Accepted: 09/01/2009] [Indexed: 12/31/2022]
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Upregulation of adrenomedullin in the spinal cord and dorsal root ganglia in the early phase of CFA-induced inflammation in rats. Pain 2009; 146:105-13. [DOI: 10.1016/j.pain.2009.07.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2008] [Revised: 07/06/2009] [Accepted: 07/13/2009] [Indexed: 02/05/2023]
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Harel F, Fu Y, Nguyen QT, Letourneau M, Perrault LP, Caron A, Fournier A, Dupuis J. Use of adrenomedullin derivatives for molecular imaging of pulmonary circulation. J Nucl Med 2008; 49:1869-74. [PMID: 18927321 DOI: 10.2967/jnumed.108.054023] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Currently, there is no low-molecular-weight agent for imaging of the pulmonary circulation. Adrenomedullin (AM) is a peptide predominantly cleared by the pulmonary circulation through specific endothelial receptors. We developed human AM derivatives radiolabeled with 99mTc and evaluated their biodistribution, plasma kinetics, and utility as pulmonary vascular imaging agents. METHODS Two derivatives radiolabeled with 99mTc were evaluated: the natural cyclic form of the peptide, to which the chelator diethylenetriaminepentaacetic acid was added (C-DTPA-AM), and the linear form, which allows direct labeling (L-AM). The compounds were injected into dogs, and the activities of the tracers in blood and in organs were determined with a nuclear medicine camera. Single-pass pulmonary clearance was measured by the indicator dilution technique. The capacity to image perfusion defects was evaluated after surgical pulmonary artery ligation. RESULTS Both derivatives were rapidly cleared from plasma, with elimination half-lives of 42 and 32 min for C-DTPA-AM and L-AM, respectively. The lungs retained most of the activity after 30 min; this activity was higher (P = 0.02) for L-AM (42% +/- 5% [mean +/- SEM]) than for C-DTPA-AM (27% +/- 1%). Lung activity slowly declined over time but was maintained after 2 h at approximately 20% for both tracers. The single-pass pulmonary clearance of plasma L-AM was 414 +/- 85 mL/min. There was a higher level of urinary excretion of L-AM than of C-DTPA-AM. After pulmonary artery ligation, perfusion defects were easily detectable by external imaging. CONCLUSION AM derivatives are promising compounds for molecular imaging of the pulmonary circulation. L-AM displayed higher levels of initial lung retention and of kidney excretion.
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Affiliation(s)
- François Harel
- Research Center, Montreal Heart Institute/Université de Montréal, Montreal, Quebec, Canada
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