Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/25252
Title: Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia.
Austin Authors: Moreira, Lucia M;Takawale, Abhijit;Hulsurkar, Mohit;Menassa, David A;Antanaviciute, Agne;Lahiri, Satadru K;Mehta, Neelam;Evans, Neil;Psarros, Constantinos;Robinson, Paul;Sparrow, Alexander J;Gillis, Marc-Antoine;Ashley, Neil;Naud, Patrice;Barallobre-Barreiro, Javier;Theofilatos, Konstantinos;Lee, Angela;Norris, Mary;Clarke, Michele V;Russell, Patricia K;Casadei, Barbara;Bhattacharya, Shoumo;Zajac, Jeffrey D ;Davey, Rachel A;Sirois, Martin;Mead, Adam;Simmons, Alison;Mayr, Manuel;Sayeed, Rana;Krasopoulos, George;Redwood, Charles;Channon, Keith M;Tardif, Jean-Claude;Wehrens, Xander H T;Nattel, Stanley;Reilly, Svetlana
Affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, UK
Biological Sciences, Faculty of Life and Environmental Sciences, University of Southampton, Southampton, UK
Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA
Research Centre, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Medicine (University of Melbourne)
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
IHU LIRYC, Fondation Bordeaux Université, Bordeaux, France
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA
Department of Medicine, Baylor College of Medicine, Houston, TX, USA
Clinical Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
Medical Research Council (MRC) Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, UK
Single-Cell Genomics Facility, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
King's British Heart Foundation Centre, King's College London, London, UK
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, UK
Medical Research Council (MRC) Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
King's British Heart Foundation Centre, King's College London, London, UK
Cardiothoracic Surgery, Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, UK
Issue Date: Nov-2020
Date: 2020-11-04
Publication information: Nature 2020; 587(7834): 460-465
Abstract: Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans1. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies2. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism3, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.
URI: https://ahro.austin.org.au/austinjspui/handle/1/25252
DOI: 10.1038/s41586-020-2890-8
ORCID: 0000-0001-8168-1538
0000-0003-0595-6661
0000-0002-9019-2215
0000-0001-9502-1530
0000-0002-5458-6065
0000-0002-3354-3314
0000-0001-6799-0553
0000-0002-6801-1617
0000-0001-8522-1002
0000-0002-0597-829X
0000-0002-2887-1874
0000-0001-5044-672X
0000-0002-5565-3311
0000-0003-1231-1239
Journal: Nature
PubMed URL: 33149301
Type: Journal Article
Appears in Collections:Journal articles

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