GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation

Myocardial dysfunction is a serious consequence of sepsis and contributes to high mortality. Currently, the molecular mechanism of myocardial dysfunction induced by sepsis remains unclear. In the present study, we investigated the role of gasdermin D (GSDMD) in cardiac dysfunction in septic mice and...

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Autores principales:	Shanshan Dai, Bozhi Ye, Lingfeng Zhong, Yanghao Chen, Guangliang Hong, Guangju Zhao, Lan Su, Zhongqiu Lu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	gasdermin D sepsis myocardial dysfunction reactive oxygen species NLRP3 inflammasome Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0b45d155824a497583a1a6e633bdaea6
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spelling	oai:doaj.org-article:0b45d155824a497583a1a6e633bdaea62021-11-08T05:38:09ZGSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation2296-634X10.3389/fcell.2021.779432https://doaj.org/article/0b45d155824a497583a1a6e633bdaea62021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.779432/fullhttps://doaj.org/toc/2296-634XMyocardial dysfunction is a serious consequence of sepsis and contributes to high mortality. Currently, the molecular mechanism of myocardial dysfunction induced by sepsis remains unclear. In the present study, we investigated the role of gasdermin D (GSDMD) in cardiac dysfunction in septic mice and the underlying mechanism. C57BL/6 wild-type (WT) mice and age-matched Gsdmd-knockout (Gsdmd-/-) mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg) to mimic sepsis. The results showed that GSDMD-NT, the functional fragment of GSDMD, was upregulated in the heart tissue of septic WT mice induced by LPS, which was accompanied by decreased cardiac function and myocardial injury, as shown by decreased ejection fraction (EF) and fractional shortening (FS) and increased cardiac troponin I (cTnI), creatine kinase isoenzymes MB (CK-MB), and lactate dehydrogenase (LDH). Gsdmd-/- mice exhibited protection against LPS-induced myocardial dysfunction and had a higher survival rate. Gsdmd deficiency attenuated LPS-induced myocardial injury and cell death. Gsdmd deficiency prevented LPS-induced the increase of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum, as well as IL-1β and TNF-α mRNA levels in myocardium. In addition, LPS-mediated inflammatory cell infiltration into the myocardium was ameliorated and activation of NF-κB signaling pathway and the NOD-like receptor protein 3 (NLPR3) inflammasome were suppressed in Gsdmd-/- mice. Further research showed that in the myocardium of LPS-induced septic mice, GSDMD-NT enrichment in mitochondria led to mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, which further regulated the activation of the NLRP3 inflammasome. In summary, our data suggest that GSDMD plays a vital role in the pathophysiology of LPS-induced myocardial dysfunction and may be a crucial target for the prevention and treatment of sepsis-induced myocardial dysfunction.Shanshan DaiBozhi YeLingfeng ZhongYanghao ChenGuangliang HongGuangju ZhaoLan SuZhongqiu LuFrontiers Media S.A.articlegasdermin Dsepsismyocardial dysfunctionreactive oxygen speciesNLRP3 inflammasomeBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	gasdermin D sepsis myocardial dysfunction reactive oxygen species NLRP3 inflammasome Biology (General) QH301-705.5
spellingShingle	gasdermin D sepsis myocardial dysfunction reactive oxygen species NLRP3 inflammasome Biology (General) QH301-705.5 Shanshan Dai Bozhi Ye Lingfeng Zhong Yanghao Chen Guangliang Hong Guangju Zhao Lan Su Zhongqiu Lu GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation
description	Myocardial dysfunction is a serious consequence of sepsis and contributes to high mortality. Currently, the molecular mechanism of myocardial dysfunction induced by sepsis remains unclear. In the present study, we investigated the role of gasdermin D (GSDMD) in cardiac dysfunction in septic mice and the underlying mechanism. C57BL/6 wild-type (WT) mice and age-matched Gsdmd-knockout (Gsdmd-/-) mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg) to mimic sepsis. The results showed that GSDMD-NT, the functional fragment of GSDMD, was upregulated in the heart tissue of septic WT mice induced by LPS, which was accompanied by decreased cardiac function and myocardial injury, as shown by decreased ejection fraction (EF) and fractional shortening (FS) and increased cardiac troponin I (cTnI), creatine kinase isoenzymes MB (CK-MB), and lactate dehydrogenase (LDH). Gsdmd-/- mice exhibited protection against LPS-induced myocardial dysfunction and had a higher survival rate. Gsdmd deficiency attenuated LPS-induced myocardial injury and cell death. Gsdmd deficiency prevented LPS-induced the increase of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum, as well as IL-1β and TNF-α mRNA levels in myocardium. In addition, LPS-mediated inflammatory cell infiltration into the myocardium was ameliorated and activation of NF-κB signaling pathway and the NOD-like receptor protein 3 (NLPR3) inflammasome were suppressed in Gsdmd-/- mice. Further research showed that in the myocardium of LPS-induced septic mice, GSDMD-NT enrichment in mitochondria led to mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, which further regulated the activation of the NLRP3 inflammasome. In summary, our data suggest that GSDMD plays a vital role in the pathophysiology of LPS-induced myocardial dysfunction and may be a crucial target for the prevention and treatment of sepsis-induced myocardial dysfunction.
format	article
author	Shanshan Dai Bozhi Ye Lingfeng Zhong Yanghao Chen Guangliang Hong Guangju Zhao Lan Su Zhongqiu Lu
author_facet	Shanshan Dai Bozhi Ye Lingfeng Zhong Yanghao Chen Guangliang Hong Guangju Zhao Lan Su Zhongqiu Lu
author_sort	Shanshan Dai
title	GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation
title_short	GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation
title_full	GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation
title_fullStr	GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation
title_full_unstemmed	GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation
title_sort	gsdmd mediates lps-induced septic myocardial dysfunction by regulating ros-dependent nlrp3 inflammasome activation
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/0b45d155824a497583a1a6e633bdaea6
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GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation

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