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心脏降钙素旁分泌信号调控心房纤维发生和心律不齐
2020-11-08 22:26

英国牛津大学Svetlana Reilly研究组发现,心脏降钙素旁分泌信号调控心房纤维发生和心律不齐。这一研究成果于2020年11月4日在线发表在国际学术期刊《自然》上。

研究人员发现,降钙素是参与骨骼代谢的甲状腺的激素产物,也由心房心肌细胞大量产生,并作为旁分泌信号,影响邻近的胶原蛋白成纤维细胞,从而控制其增殖和分泌细胞外基质蛋白。小鼠降钙素受体信号传导的整体破坏会导致心房纤维化,并增加对房颤的敏感性。在心房中特异性敲低肝激酶B1的小鼠中,降钙素的心房特异性敲低会促进心房纤维化并增加和延长自发性心房纤颤的发生,而降钙素的心房特异性过表达则可防止心房纤维化和房颤。
 
与具有正常心律的对照组相比,持续性心房颤动病人的心肌降钙素水平降低了六倍,而成纤维细胞膜中的降钙素受体丢失。尽管人类心房成纤维细胞的转录组分析显示降钙素暴露后变化不大,但是蛋白质组学分析显示胞外基质蛋白以及与纤维形成、感染和免疫反应以及转录调控有关途径的广泛变化。因此,恢复中断的心肌降钙素信号传导可能成为房颤患者的治疗途径。
 
据了解,心房颤动是最常见的心律不齐,是导致死亡率和发病率,尤其是人类中风的重要原因。心房组织纤维化是心房纤颤的主要病理生理特征,也妨碍了其治疗。由于目前疗法的不足,人们对潜在的分子机制了解甚少,值得进行研究。
 
附:英文原文

Title: Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia

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

Issue&Volume: 2020-11-04

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. Heart atria produce a large pool of calcitonin (previously well-recognized as a thyroid-secreted hormone with roles in calcium and bone metabolism) that in the heart acts as a paracrine signal controlling atrial fibrosis and fibrillation.

DOI: 10.1038/s41586-020-2890-8

Source: https://www.nature.com/articles/s41586-020-2890-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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