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Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia

Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia
Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia
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.
0028-0836
460-465
Moreira, Lucia M.
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Takawale, Abhijit
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Hulsurkar, Mohit
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Menassa, David
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Psarros, Constantinos
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Robinson, Paul
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Krasopoulos, George
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Redwood, Charles
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Channon, Keith M.
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Nattel, Stanley
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Moreira, Lucia M.
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Menassa, David
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Barallobre-Barreiro, Javier
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Theofilatos, Konstantinos
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Casadei, Barbara
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Zajac, Jeffrey D.
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Mead, Adam
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Sayeed, Rana
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Krasopoulos, George
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Redwood, Charles
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Channon, Keith M.
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Tardif, Jean-Claude
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Nattel, Stanley
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Reilly, Svetlana
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Moreira, Lucia M., Takawale, Abhijit, Hulsurkar, Mohit, Menassa, David, Antanaviciute, Agne, Lahiri, Satadru K., Mehta, Neelam, Evans, Neil, Psarros, Constantinos, Robinson, Paul, Sparrow, Alex, 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 and Reilly, Svetlana (2020) Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia. Nature, 587 (7834), 460-465. (doi:10.1038/s41586-020-2890-8).

Record type: Article

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.

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349018_3_merged_1595863646 - Accepted Manuscript
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Accepted/In Press date: 13 August 2020
e-pub ahead of print date: 4 November 2020
Published date: 19 November 2020

Identifiers

Local EPrints ID: 444792
URI: http://eprints.soton.ac.uk/id/eprint/444792
ISSN: 0028-0836
PURE UUID: 482fc519-6c9d-474a-ba2c-c3785c908ad8

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Date deposited: 05 Nov 2020 17:30
Last modified: 17 Mar 2024 05:50

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Contributors

Author: Lucia M. Moreira
Author: Abhijit Takawale
Author: Mohit Hulsurkar
Author: David Menassa
Author: Agne Antanaviciute
Author: Satadru K. Lahiri
Author: Neelam Mehta
Author: Neil Evans
Author: Constantinos Psarros
Author: Paul Robinson
Author: Alex Sparrow
Author: Marc-Antoine Gillis
Author: Neil Ashley
Author: Patrice Naud
Author: Javier Barallobre-Barreiro
Author: Konstantinos Theofilatos
Author: Angela Lee
Author: Mary Norris
Author: Michele V. Clarke
Author: Patricia K. Russell
Author: Barbara Casadei
Author: Shoumo Bhattacharya
Author: Jeffrey D. Zajac
Author: Rachel A. Davey
Author: Martin Sirois
Author: Adam Mead
Author: Alison Simmons
Author: Manuel Mayr
Author: Rana Sayeed
Author: George Krasopoulos
Author: Charles Redwood
Author: Keith M. Channon
Author: Jean-Claude Tardif
Author: Xander H.T. Wehrens
Author: Stanley Nattel
Author: Svetlana Reilly

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