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Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction

BACKGROUND: As a pattern recognition receptor, Toll‐like receptor 7 (TLR7) widely presented in the endosomal membrane of various cells. However, the precise role and mechanism of TLR7 in septic cardiomyopathy remain unknown. This study aims to determine the role of TLR7 in cardiac dysfunction during...

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Autores principales: Saiyang, Xie, Qingqing, Wu, man, Xu, Chen, Liu, Min, Zhang, Yun, Xing, Wenke, Shi, Haiming, Wu, Xiaofeng, Zeng, Si, Chen, Haipeng, Guo, Wei, Deng, Qizhu, Tang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775988/
https://www.ncbi.nlm.nih.gov/pubmed/33463061
http://dx.doi.org/10.1002/ctm2.266
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author Saiyang, Xie
Qingqing, Wu
man, Xu
Chen, Liu
Min, Zhang
Yun, Xing
Wenke, Shi
Haiming, Wu
Xiaofeng, Zeng
Si, Chen
Haipeng, Guo
Wei, Deng
Qizhu, Tang
author_facet Saiyang, Xie
Qingqing, Wu
man, Xu
Chen, Liu
Min, Zhang
Yun, Xing
Wenke, Shi
Haiming, Wu
Xiaofeng, Zeng
Si, Chen
Haipeng, Guo
Wei, Deng
Qizhu, Tang
author_sort Saiyang, Xie
collection PubMed
description BACKGROUND: As a pattern recognition receptor, Toll‐like receptor 7 (TLR7) widely presented in the endosomal membrane of various cells. However, the precise role and mechanism of TLR7 in septic cardiomyopathy remain unknown. This study aims to determine the role of TLR7 in cardiac dysfunction during sepsis and explore the mechanism of TLR7 in septic cardiomyopathy. METHODS: We generated a mouse model of septic cardiomyopathy by challenging with lipopolysaccharide (LPS). TLR7‐knockout (TLR7(−/−)), wild‐type (WT) mice, cardiac‐specific TLR7‐transgenic (cTG‐TLR7) overexpression, and littermates WT (LWT) mice were subjected to septic model. Additionally, to verify the role and mechanism of TLR7 in vitro, we transfected neonatal rat ventricular myocytes (NRVMs) with Ad‐TLR7 and TLR7 siRNA before LPS administration. The effects of TLR7 were assessed by Ca(2+) imaging, western blotting, immunostaining, and quantitative real‐time polymerase chain reaction (qPCR). RESULTS: We found that TLR7 knockout markedly exacerbated sepsis‐induced systolic dysfunction. Moreover, cardiomyocytes isolated from TLR7(−/−) mice displayed weaker Ca(2+) handling than that in WT mice in response to LPS. Conversely, TLR7 overexpression alleviated LPS‐induced systolic dysfunction, and loxoribine (TLR7‐specific agonist) improved LPS‐induced cardiac dysfunction. Mechanistically, these optimized effects were associated with enhanced the adenosine (cAMP)‐protein kinase A (PKA) pathway, which upregulated phosphorylate‐phospholamban (p‐PLN) (Ser16) and promoted sarco/endoplasmic reticulum Ca(2+) ATPase (Serca) and Ryanodine Receptor 2 (RyR2) expression in the sarcoplasmic reticulum (SR), and ultimately restored Ca(2+) handling in response to sepsis. While improved Ca(2+) handling was abrogated after H89 (a specific PKA inhibitor) pretreatment in cardiomyocytes isolated from cTG‐TLR7 mice. Consistently, TLR7 overexpression improved LPS‐induced Ca(2+)‐handling decrement in NRVMs. Nevertheless, TLR7 knockdown showed a deteriorative phenotype. CONCLUSIONS: Our data demonstrated that activation of TLR7 protected against sepsis‐induced cardiac dysfunction through promoting cAMP‐PKA‐PLN pathway, and we revealed that TLR7 might be a novel therapeutic target to block the septic cardiomyopathy and support systolic function during sepsis.
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spelling pubmed-77759882021-01-07 Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction Saiyang, Xie Qingqing, Wu man, Xu Chen, Liu Min, Zhang Yun, Xing Wenke, Shi Haiming, Wu Xiaofeng, Zeng Si, Chen Haipeng, Guo Wei, Deng Qizhu, Tang Clin Transl Med Research Articles BACKGROUND: As a pattern recognition receptor, Toll‐like receptor 7 (TLR7) widely presented in the endosomal membrane of various cells. However, the precise role and mechanism of TLR7 in septic cardiomyopathy remain unknown. This study aims to determine the role of TLR7 in cardiac dysfunction during sepsis and explore the mechanism of TLR7 in septic cardiomyopathy. METHODS: We generated a mouse model of septic cardiomyopathy by challenging with lipopolysaccharide (LPS). TLR7‐knockout (TLR7(−/−)), wild‐type (WT) mice, cardiac‐specific TLR7‐transgenic (cTG‐TLR7) overexpression, and littermates WT (LWT) mice were subjected to septic model. Additionally, to verify the role and mechanism of TLR7 in vitro, we transfected neonatal rat ventricular myocytes (NRVMs) with Ad‐TLR7 and TLR7 siRNA before LPS administration. The effects of TLR7 were assessed by Ca(2+) imaging, western blotting, immunostaining, and quantitative real‐time polymerase chain reaction (qPCR). RESULTS: We found that TLR7 knockout markedly exacerbated sepsis‐induced systolic dysfunction. Moreover, cardiomyocytes isolated from TLR7(−/−) mice displayed weaker Ca(2+) handling than that in WT mice in response to LPS. Conversely, TLR7 overexpression alleviated LPS‐induced systolic dysfunction, and loxoribine (TLR7‐specific agonist) improved LPS‐induced cardiac dysfunction. Mechanistically, these optimized effects were associated with enhanced the adenosine (cAMP)‐protein kinase A (PKA) pathway, which upregulated phosphorylate‐phospholamban (p‐PLN) (Ser16) and promoted sarco/endoplasmic reticulum Ca(2+) ATPase (Serca) and Ryanodine Receptor 2 (RyR2) expression in the sarcoplasmic reticulum (SR), and ultimately restored Ca(2+) handling in response to sepsis. While improved Ca(2+) handling was abrogated after H89 (a specific PKA inhibitor) pretreatment in cardiomyocytes isolated from cTG‐TLR7 mice. Consistently, TLR7 overexpression improved LPS‐induced Ca(2+)‐handling decrement in NRVMs. Nevertheless, TLR7 knockdown showed a deteriorative phenotype. CONCLUSIONS: Our data demonstrated that activation of TLR7 protected against sepsis‐induced cardiac dysfunction through promoting cAMP‐PKA‐PLN pathway, and we revealed that TLR7 might be a novel therapeutic target to block the septic cardiomyopathy and support systolic function during sepsis. John Wiley and Sons Inc. 2021-01-01 /pmc/articles/PMC7775988/ /pubmed/33463061 http://dx.doi.org/10.1002/ctm2.266 Text en © 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Saiyang, Xie
Qingqing, Wu
man, Xu
Chen, Liu
Min, Zhang
Yun, Xing
Wenke, Shi
Haiming, Wu
Xiaofeng, Zeng
Si, Chen
Haipeng, Guo
Wei, Deng
Qizhu, Tang
Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction
title Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction
title_full Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction
title_fullStr Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction
title_full_unstemmed Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction
title_short Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction
title_sort activation of toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775988/
https://www.ncbi.nlm.nih.gov/pubmed/33463061
http://dx.doi.org/10.1002/ctm2.266
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