Cargando…

The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism

AIM: Sigma-1 receptors have been investigated and shown to play a protective role in both depression and cardiovascular disease. SA4503, known as a σ1 receptor agonist, regulates cardiac calcium and potassium channels in rat models of depression. However, it remains unknown whether SA4503 can allevi...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Xin, Qu, Chuan, Shi, Shaobo, Ye, Tianxin, Wang, Linglin, Liu, Steven, Zhang, Cui, Liang, Jinjun, Hu, Dan, Yang, Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870537/
https://www.ncbi.nlm.nih.gov/pubmed/31803058
http://dx.doi.org/10.3389/fphys.2019.01346
_version_ 1783472402402902016
author Liu, Xin
Qu, Chuan
Shi, Shaobo
Ye, Tianxin
Wang, Linglin
Liu, Steven
Zhang, Cui
Liang, Jinjun
Hu, Dan
Yang, Bo
author_facet Liu, Xin
Qu, Chuan
Shi, Shaobo
Ye, Tianxin
Wang, Linglin
Liu, Steven
Zhang, Cui
Liang, Jinjun
Hu, Dan
Yang, Bo
author_sort Liu, Xin
collection PubMed
description AIM: Sigma-1 receptors have been investigated and shown to play a protective role in both depression and cardiovascular disease. SA4503, known as a σ1 receptor agonist, regulates cardiac calcium and potassium channels in rat models of depression. However, it remains unknown whether SA4503 can alleviate myocardial inflammation or conduction junctions in the atrium after exposure to chronic mild stress. METHODS AND RESULTS: Sprague-Dawley male rats received 28-day treatment with SA4503, simultaneously with chronic mild stress. Behavior measurements were assessed after the daily doses. Additionally, a multielectrode array assessment, electrophysiological study, immunohistochemistry analysis, histological analysis, and Western blot analysis were performed. Depression rats’ hearts showed abnormal electrical activity, including disordered excitation propagation and prolonged total activation time (TAT). In addition, atrial arrhythmias (AAs), induced by burst stimulation, showed higher incidence and longer duration in the depression group compared to the control group. These changes were related to reduced conduction junctions and enhanced spatial heterogeneity. Importantly, depressed rat hearts showed greater expression of inflammatory factors (TGF-α, IL-6, and TGF-β), more collagen distribution in the extracellular matrix, and lower expression of gap junction proteins (CX40 and CX43). Furthermore, SA4503 partially mitigated the above indices in the depression group (P < 0.01 for all groups). CONCLUSION: These findings show the effects of the σ1R agonist SA4503; it alleviates atrial myocardial inflammation and conduction junctions after chronic mild stress. SA4503 may be the promising pharmacological agent to treat depression-related AAs by increasing conduction function, improving the expression of connexin 40 and 43, and reducing cardiac myocardial inflammation.
format Online
Article
Text
id pubmed-6870537
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-68705372019-12-04 The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism Liu, Xin Qu, Chuan Shi, Shaobo Ye, Tianxin Wang, Linglin Liu, Steven Zhang, Cui Liang, Jinjun Hu, Dan Yang, Bo Front Physiol Physiology AIM: Sigma-1 receptors have been investigated and shown to play a protective role in both depression and cardiovascular disease. SA4503, known as a σ1 receptor agonist, regulates cardiac calcium and potassium channels in rat models of depression. However, it remains unknown whether SA4503 can alleviate myocardial inflammation or conduction junctions in the atrium after exposure to chronic mild stress. METHODS AND RESULTS: Sprague-Dawley male rats received 28-day treatment with SA4503, simultaneously with chronic mild stress. Behavior measurements were assessed after the daily doses. Additionally, a multielectrode array assessment, electrophysiological study, immunohistochemistry analysis, histological analysis, and Western blot analysis were performed. Depression rats’ hearts showed abnormal electrical activity, including disordered excitation propagation and prolonged total activation time (TAT). In addition, atrial arrhythmias (AAs), induced by burst stimulation, showed higher incidence and longer duration in the depression group compared to the control group. These changes were related to reduced conduction junctions and enhanced spatial heterogeneity. Importantly, depressed rat hearts showed greater expression of inflammatory factors (TGF-α, IL-6, and TGF-β), more collagen distribution in the extracellular matrix, and lower expression of gap junction proteins (CX40 and CX43). Furthermore, SA4503 partially mitigated the above indices in the depression group (P < 0.01 for all groups). CONCLUSION: These findings show the effects of the σ1R agonist SA4503; it alleviates atrial myocardial inflammation and conduction junctions after chronic mild stress. SA4503 may be the promising pharmacological agent to treat depression-related AAs by increasing conduction function, improving the expression of connexin 40 and 43, and reducing cardiac myocardial inflammation. Frontiers Media S.A. 2019-11-14 /pmc/articles/PMC6870537/ /pubmed/31803058 http://dx.doi.org/10.3389/fphys.2019.01346 Text en Copyright © 2019 Liu, Qu, Shi, Ye, Wang, Liu, Zhang, Liang, Hu and Yang. 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
Liu, Xin
Qu, Chuan
Shi, Shaobo
Ye, Tianxin
Wang, Linglin
Liu, Steven
Zhang, Cui
Liang, Jinjun
Hu, Dan
Yang, Bo
The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism
title The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism
title_full The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism
title_fullStr The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism
title_full_unstemmed The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism
title_short The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism
title_sort reversal effect of sigma-1 receptor (s1r) agonist, sa4503, on atrial fibrillation after depression and its underlying mechanism
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870537/
https://www.ncbi.nlm.nih.gov/pubmed/31803058
http://dx.doi.org/10.3389/fphys.2019.01346
work_keys_str_mv AT liuxin thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT quchuan thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT shishaobo thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT yetianxin thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT wanglinglin thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT liusteven thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT zhangcui thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT liangjinjun thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT hudan thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT yangbo thereversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT liuxin reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT quchuan reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT shishaobo reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT yetianxin reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT wanglinglin reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT liusteven reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT zhangcui reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT liangjinjun reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT hudan reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism
AT yangbo reversaleffectofsigma1receptors1ragonistsa4503onatrialfibrillationafterdepressionanditsunderlyingmechanism