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PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation

Left atrial appendage (LAA) thrombus detachment resulting in intracranial embolism is a major complication of atrial fibrillation (AF). Endocardial endothelial cell (EEC) injury leads to thrombosis, whereas autophagy protects against EEC dysfunction. However, the role and underlying mechanisms of au...

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Autores principales: Sun, Mengjia, Chen, Zhen, Song, Yuanbin, Zhang, Bo, Yang, Jie, Tan, Hu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395636/
https://www.ncbi.nlm.nih.gov/pubmed/36017337
http://dx.doi.org/10.3389/fphys.2022.960480
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author Sun, Mengjia
Chen, Zhen
Song, Yuanbin
Zhang, Bo
Yang, Jie
Tan, Hu
author_facet Sun, Mengjia
Chen, Zhen
Song, Yuanbin
Zhang, Bo
Yang, Jie
Tan, Hu
author_sort Sun, Mengjia
collection PubMed
description Left atrial appendage (LAA) thrombus detachment resulting in intracranial embolism is a major complication of atrial fibrillation (AF). Endocardial endothelial cell (EEC) injury leads to thrombosis, whereas autophagy protects against EEC dysfunction. However, the role and underlying mechanisms of autophagy in EECs during AF have not been elucidated. In this study, we isolated EECs from AF model mice and observed reduced autophagic flux and intracellular calcium concentrations in EECs from AF mice. In addition, we detected an increased expression of the mechanosensitive protein PLXND1 in the cytomembranes of EECs. PLXND1 served as a scaffold protein to bind with ORAI1 and further decreased ORAI1-mediated calcium influx. The decrease in the calcium influx-mediated phosphorylation of CAMK2 is associated with the inhibition of autophagy, which results in EEC dysfunction in AF. Our study demonstrated that the change in PLXND1 expression contributes to intracellular calcium dyshomeostasis, which inhibits autophagy flux and results in EEC dysfunction in AF. This study provides a potential intervention target for EEC dysfunction to prevent and treat intracardiac thrombosis in AF and its complications.
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spelling pubmed-93956362022-08-24 PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation Sun, Mengjia Chen, Zhen Song, Yuanbin Zhang, Bo Yang, Jie Tan, Hu Front Physiol Physiology Left atrial appendage (LAA) thrombus detachment resulting in intracranial embolism is a major complication of atrial fibrillation (AF). Endocardial endothelial cell (EEC) injury leads to thrombosis, whereas autophagy protects against EEC dysfunction. However, the role and underlying mechanisms of autophagy in EECs during AF have not been elucidated. In this study, we isolated EECs from AF model mice and observed reduced autophagic flux and intracellular calcium concentrations in EECs from AF mice. In addition, we detected an increased expression of the mechanosensitive protein PLXND1 in the cytomembranes of EECs. PLXND1 served as a scaffold protein to bind with ORAI1 and further decreased ORAI1-mediated calcium influx. The decrease in the calcium influx-mediated phosphorylation of CAMK2 is associated with the inhibition of autophagy, which results in EEC dysfunction in AF. Our study demonstrated that the change in PLXND1 expression contributes to intracellular calcium dyshomeostasis, which inhibits autophagy flux and results in EEC dysfunction in AF. This study provides a potential intervention target for EEC dysfunction to prevent and treat intracardiac thrombosis in AF and its complications. Frontiers Media S.A. 2022-08-09 /pmc/articles/PMC9395636/ /pubmed/36017337 http://dx.doi.org/10.3389/fphys.2022.960480 Text en Copyright © 2022 Sun, Chen, Song, Zhang, Yang and Tan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Sun, Mengjia
Chen, Zhen
Song, Yuanbin
Zhang, Bo
Yang, Jie
Tan, Hu
PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation
title PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation
title_full PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation
title_fullStr PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation
title_full_unstemmed PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation
title_short PLXND1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation
title_sort plxnd1-mediated calcium dyshomeostasis impairs endocardial endothelial autophagy in atrial fibrillation
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395636/
https://www.ncbi.nlm.nih.gov/pubmed/36017337
http://dx.doi.org/10.3389/fphys.2022.960480
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