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TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity
SIMPLE SUMMARY: We described the existence of an integrated Beclin 1, TLR9, and SIRT3 network involving autophagy, oxidative stress, and mitochondria that is essential for empagliflozin to protect against doxorubicin toxicity in the heart. Empagliflozin treatment increases the abundance of mitochond...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693736/ https://www.ncbi.nlm.nih.gov/pubmed/33138323 http://dx.doi.org/10.3390/biology9110369 |
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author | Wang, Chao-Yung Chen, Chun-Chi Lin, Mei-Hsiu Su, Hui-Ting Ho, Ming-Yun Yeh, Jih-Kai Tsai, Ming-Lung Hsieh, I-Chang Wen, Ming-Shien |
author_facet | Wang, Chao-Yung Chen, Chun-Chi Lin, Mei-Hsiu Su, Hui-Ting Ho, Ming-Yun Yeh, Jih-Kai Tsai, Ming-Lung Hsieh, I-Chang Wen, Ming-Shien |
author_sort | Wang, Chao-Yung |
collection | PubMed |
description | SIMPLE SUMMARY: We described the existence of an integrated Beclin 1, TLR9, and SIRT3 network involving autophagy, oxidative stress, and mitochondria that is essential for empagliflozin to protect against doxorubicin toxicity in the heart. Empagliflozin treatment increases the abundance of mitochondrial SIRT3 and enhances the activation of TLR9 to bind with Beclin 1, triggering communication to the autophagic, immune system, and inflammatory machinery. From a therapeutic standpoint, SIRT3 loss-of-function variant DCM patients lose the empagliflozin-protective effects, since SIRT3 is implicated in modern world diseases, such as aging, circadian disturbance, and obesity. ABSTRACT: Large cardiovascular outcome trials have reported favorable effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on heart failure. To study the potential mechanism of the SGLT2 inhibition in heart failure, we used the murine doxorubicin-induced cardiomyopathy model and identified the toll-like receptor 9 (TLR9), NAD-dependent deacetylase sirtuin-3 (SIRT3), and Beclin 1, acting in a complex together in response to empagliflozin treatment. The interactions and implications in mitochondrial function were evaluated with TLR9 deficient, SIRT3 deficient, Beclin 1 haplodeficient, and autophagy reporter mice and confirmed in a patient with SIRT3 point mutation and reduced enzymatic activity. The SGLT2 inhibitor, empagliflozin, protects the heart from doxorubicin cardiomyopathy in mice, by acting through a novel Beclin 1-toll-like receptor (TLR) 9-sirtuin-(SIRT) 3 axis. TLR9 and SIRT3 were both essential for the protective effects of empagliflozin. The dilated cardiomyopathy patient with SIRT3 point mutation and reduced enzymatic activity is associated with reduced TLR9 activation and the absence of mitochondrial responses in the heart after the SGLT2 inhibitor treatment. Our data indicate a dynamic communication between autophagy and Beclin 1-TLR9-SIRT3 complexes in the mitochondria in response to empagliflozin that may serve as a potential treatment strategy for heart failure. |
format | Online Article Text |
id | pubmed-7693736 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76937362020-11-28 TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity Wang, Chao-Yung Chen, Chun-Chi Lin, Mei-Hsiu Su, Hui-Ting Ho, Ming-Yun Yeh, Jih-Kai Tsai, Ming-Lung Hsieh, I-Chang Wen, Ming-Shien Biology (Basel) Article SIMPLE SUMMARY: We described the existence of an integrated Beclin 1, TLR9, and SIRT3 network involving autophagy, oxidative stress, and mitochondria that is essential for empagliflozin to protect against doxorubicin toxicity in the heart. Empagliflozin treatment increases the abundance of mitochondrial SIRT3 and enhances the activation of TLR9 to bind with Beclin 1, triggering communication to the autophagic, immune system, and inflammatory machinery. From a therapeutic standpoint, SIRT3 loss-of-function variant DCM patients lose the empagliflozin-protective effects, since SIRT3 is implicated in modern world diseases, such as aging, circadian disturbance, and obesity. ABSTRACT: Large cardiovascular outcome trials have reported favorable effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on heart failure. To study the potential mechanism of the SGLT2 inhibition in heart failure, we used the murine doxorubicin-induced cardiomyopathy model and identified the toll-like receptor 9 (TLR9), NAD-dependent deacetylase sirtuin-3 (SIRT3), and Beclin 1, acting in a complex together in response to empagliflozin treatment. The interactions and implications in mitochondrial function were evaluated with TLR9 deficient, SIRT3 deficient, Beclin 1 haplodeficient, and autophagy reporter mice and confirmed in a patient with SIRT3 point mutation and reduced enzymatic activity. The SGLT2 inhibitor, empagliflozin, protects the heart from doxorubicin cardiomyopathy in mice, by acting through a novel Beclin 1-toll-like receptor (TLR) 9-sirtuin-(SIRT) 3 axis. TLR9 and SIRT3 were both essential for the protective effects of empagliflozin. The dilated cardiomyopathy patient with SIRT3 point mutation and reduced enzymatic activity is associated with reduced TLR9 activation and the absence of mitochondrial responses in the heart after the SGLT2 inhibitor treatment. Our data indicate a dynamic communication between autophagy and Beclin 1-TLR9-SIRT3 complexes in the mitochondria in response to empagliflozin that may serve as a potential treatment strategy for heart failure. MDPI 2020-10-29 /pmc/articles/PMC7693736/ /pubmed/33138323 http://dx.doi.org/10.3390/biology9110369 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wang, Chao-Yung Chen, Chun-Chi Lin, Mei-Hsiu Su, Hui-Ting Ho, Ming-Yun Yeh, Jih-Kai Tsai, Ming-Lung Hsieh, I-Chang Wen, Ming-Shien TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity |
title | TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity |
title_full | TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity |
title_fullStr | TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity |
title_full_unstemmed | TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity |
title_short | TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity |
title_sort | tlr9 binding to beclin 1 and mitochondrial sirt3 by a sodium-glucose co-transporter 2 inhibitor protects the heart from doxorubicin toxicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693736/ https://www.ncbi.nlm.nih.gov/pubmed/33138323 http://dx.doi.org/10.3390/biology9110369 |
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