STING protects against cardiac dysfunction and remodelling by blocking autophagy

Abstract Background Heart failure, which is characterized by cardiac remodelling, is one of the most common chronic diseases in the aged. Stimulator of interferon genes (STING) acts as an indispensable molecule modulating immune response and inflammation in many diseases. However, the effects of STI...

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Autores principales:	Rui Xiong, Ning Li, Lei Chen, Wei Wang, Bo Wang, Wenyang Jiang, Qing Geng
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	STING Cardiac remodelling Inflammation Autophagy ULK1 Medicine R Cytology QH573-671
Acceso en línea:	https://doaj.org/article/0540ee358583444eb7a494c04aac8a33
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spelling	oai:doaj.org-article:0540ee358583444eb7a494c04aac8a332021-11-14T12:15:34ZSTING protects against cardiac dysfunction and remodelling by blocking autophagy10.1186/s12964-021-00793-01478-811Xhttps://doaj.org/article/0540ee358583444eb7a494c04aac8a332021-11-01T00:00:00Zhttps://doi.org/10.1186/s12964-021-00793-0https://doaj.org/toc/1478-811XAbstract Background Heart failure, which is characterized by cardiac remodelling, is one of the most common chronic diseases in the aged. Stimulator of interferon genes (STING) acts as an indispensable molecule modulating immune response and inflammation in many diseases. However, the effects of STING on cardiomyopathy, especially cardiac remodelling are still largely unknown. This study was designed to investigate whether STING could affect cardiac remodelling and to explore the potential mechanisms. Methods In vivo, aortic binding (AB) surgery was performed to construct the mice model of cardiac remodelling. A DNA microinjection system was used to trigger STING overexpression in mice. The STING mRNA and protein expression levels in mice heart were measured, and the cardiac hypertrophy, fibrosis, inflammation and cardiac function were also evaluated. In vitro, cardiomyocytes stimulated by Ang II and cardiac fibroblasts stimulated by TGF-β to performed to further study effects of STING on cardiac hypertrophy and fibroblast. In terms of mechanisms, the level of autophagy was detected in mice challenged with AB. Rapamycin, a canonical autophagy inducer, intraperitoneal injected into mice to study possible potential pathway. Results In vivo, the STING mRNA and protein expression levels in mice heart challenged with AB for 6 weeks were significantly increased. STING overexpression significantly mitigated cardiac hypertrophy, fibrosis and inflammation, apart from improving cardiac function. In vitro, experiments further disclosed that STING overexpression in cardiomyocytes induced by Ang II significantly inhibited the level of cardiomyocyte cross-section area and the ANP mRNA. Meanwhile, TGF-β-induced the increase of α-SMA content and collagen synthesis in cardiac fibroblasts could be also blocked by STING overexpression. In terms of mechanisms, mice challenged with AB showed higher level of autophagy compared with the normal mice. However, STING overexpression could reverse the activation of autophagy triggered by AB. Rapamycin, a canonical autophagy inducer, offset the cardioprotective effects of STING in mice challenged with AB. Finally, further experiments unveiled that STING may inhibit autophagy by phosphorylating ULK1 on serine757. Conclusions STING may prevent cardiac remodelling induced by pressure overload by inhibiting autophagy, which could be a promising therapeutic target in heart failure. Video AbstractRui XiongNing LiLei ChenWei WangBo WangWenyang JiangQing GengBMCarticleSTINGCardiac remodellingInflammationAutophagyULK1MedicineRCytologyQH573-671ENCell Communication and Signaling, Vol 19, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	STING Cardiac remodelling Inflammation Autophagy ULK1 Medicine R Cytology QH573-671
spellingShingle	STING Cardiac remodelling Inflammation Autophagy ULK1 Medicine R Cytology QH573-671 Rui Xiong Ning Li Lei Chen Wei Wang Bo Wang Wenyang Jiang Qing Geng STING protects against cardiac dysfunction and remodelling by blocking autophagy
description	Abstract Background Heart failure, which is characterized by cardiac remodelling, is one of the most common chronic diseases in the aged. Stimulator of interferon genes (STING) acts as an indispensable molecule modulating immune response and inflammation in many diseases. However, the effects of STING on cardiomyopathy, especially cardiac remodelling are still largely unknown. This study was designed to investigate whether STING could affect cardiac remodelling and to explore the potential mechanisms. Methods In vivo, aortic binding (AB) surgery was performed to construct the mice model of cardiac remodelling. A DNA microinjection system was used to trigger STING overexpression in mice. The STING mRNA and protein expression levels in mice heart were measured, and the cardiac hypertrophy, fibrosis, inflammation and cardiac function were also evaluated. In vitro, cardiomyocytes stimulated by Ang II and cardiac fibroblasts stimulated by TGF-β to performed to further study effects of STING on cardiac hypertrophy and fibroblast. In terms of mechanisms, the level of autophagy was detected in mice challenged with AB. Rapamycin, a canonical autophagy inducer, intraperitoneal injected into mice to study possible potential pathway. Results In vivo, the STING mRNA and protein expression levels in mice heart challenged with AB for 6 weeks were significantly increased. STING overexpression significantly mitigated cardiac hypertrophy, fibrosis and inflammation, apart from improving cardiac function. In vitro, experiments further disclosed that STING overexpression in cardiomyocytes induced by Ang II significantly inhibited the level of cardiomyocyte cross-section area and the ANP mRNA. Meanwhile, TGF-β-induced the increase of α-SMA content and collagen synthesis in cardiac fibroblasts could be also blocked by STING overexpression. In terms of mechanisms, mice challenged with AB showed higher level of autophagy compared with the normal mice. However, STING overexpression could reverse the activation of autophagy triggered by AB. Rapamycin, a canonical autophagy inducer, offset the cardioprotective effects of STING in mice challenged with AB. Finally, further experiments unveiled that STING may inhibit autophagy by phosphorylating ULK1 on serine757. Conclusions STING may prevent cardiac remodelling induced by pressure overload by inhibiting autophagy, which could be a promising therapeutic target in heart failure. Video Abstract
format	article
author	Rui Xiong Ning Li Lei Chen Wei Wang Bo Wang Wenyang Jiang Qing Geng
author_facet	Rui Xiong Ning Li Lei Chen Wei Wang Bo Wang Wenyang Jiang Qing Geng
author_sort	Rui Xiong
title	STING protects against cardiac dysfunction and remodelling by blocking autophagy
title_short	STING protects against cardiac dysfunction and remodelling by blocking autophagy
title_full	STING protects against cardiac dysfunction and remodelling by blocking autophagy
title_fullStr	STING protects against cardiac dysfunction and remodelling by blocking autophagy
title_full_unstemmed	STING protects against cardiac dysfunction and remodelling by blocking autophagy
title_sort	sting protects against cardiac dysfunction and remodelling by blocking autophagy
publisher	BMC
publishDate	2021
url	https://doaj.org/article/0540ee358583444eb7a494c04aac8a33
work_keys_str_mv	AT ruixiong stingprotectsagainstcardiacdysfunctionandremodellingbyblockingautophagy AT ningli stingprotectsagainstcardiacdysfunctionandremodellingbyblockingautophagy AT leichen stingprotectsagainstcardiacdysfunctionandremodellingbyblockingautophagy AT weiwang stingprotectsagainstcardiacdysfunctionandremodellingbyblockingautophagy AT bowang stingprotectsagainstcardiacdysfunctionandremodellingbyblockingautophagy AT wenyangjiang stingprotectsagainstcardiacdysfunctionandremodellingbyblockingautophagy AT qinggeng stingprotectsagainstcardiacdysfunctionandremodellingbyblockingautophagy
_version_	1718429328259153920

STING protects against cardiac dysfunction and remodelling by blocking autophagy

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