Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury

Abstract Background Myocardial reperfusion injury is often accompanied by cell death and inflammatory reactions. Recently, pyroptosis is gradually recognized as pivotal role in cardiovascular disease. However, little is known about the regulatory role of beclin1 in the control of caspase-4 activatio...

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Autores principales:	Wenjing Sun, Hongquan Lu, Shujuan Dong, Rui Li, Yingjie Chu, Nan Wang, Yu Zhao, Yabin Zhang, Limeiting Wang, Lin Sun, Di Lu
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Ischemia/reperfusion Caspase-4 inflammasome Pyroptosis Beclin1 Medicine R Cytology QH573-671
Acceso en línea:	https://doaj.org/article/7667ec6a30c6436e9ff57fda2deb58f7
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spelling	oai:doaj.org-article:7667ec6a30c6436e9ff57fda2deb58f72021-11-08T10:44:49ZBeclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury10.1186/s12964-021-00786-z1478-811Xhttps://doaj.org/article/7667ec6a30c6436e9ff57fda2deb58f72021-11-01T00:00:00Zhttps://doi.org/10.1186/s12964-021-00786-zhttps://doaj.org/toc/1478-811XAbstract Background Myocardial reperfusion injury is often accompanied by cell death and inflammatory reactions. Recently, pyroptosis is gradually recognized as pivotal role in cardiovascular disease. However, little is known about the regulatory role of beclin1 in the control of caspase-4 activation and pyroptosis. The present study confirmed whether beclin1 regulates caspase-4 mediated pyroptosis and thereby protects Human Cardiac microvascular endothelial cells (HCMECs) against injury. Methods TTC and Evan's blue dye, western blot, immunofluorescence and immunohistochemistry staining were performed in wild mice and transgenic mice with overexpression of beclin 1(BECN1-Tg). CMECs were transfected with a beclin1 lentivirus. The cell cytotoxicity was analyzed by LDH-Cytotoxicity Assay Kit. The protein levels of autophagy protein (Beclin1, p62 and LC3II/LC3I) and caspase-4/GSDMD pathway were determined by western blot. Autophagic vacuoles in cells were monitored with RFP-GFP-LC3 using fluorescence microscope. Results I/R caused caspase-4 activity and gasdermin D expression increase in vivo and in vitro. Overexpression of beclin1 in heart tissue and CMECs suppressed the caspase-4 activity and decreased the levels of gasdermin D; meanwhile beclin1 overexpression also reduced IL-1β levels, promoted autophagy (p62 expression was inhibited while LC3II expression was increased) in the heart and CMECs. Interestingly, beclin1 overexpression increased animal survival and attenuated myocardial infarct size (45 ± 6.13 vs 22 ± 4.37), no-reflow area (39 ± 5.22 vs 16 ± 2.54) post-myocardial ischemia reperfusion. Conclusions Induction of beclin-1 signaling can be a potential therapeutic target in myocardial reperfusion-induced microvascular injury. Video AbstractWenjing SunHongquan LuShujuan DongRui LiYingjie ChuNan WangYu ZhaoYabin ZhangLimeiting WangLin SunDi LuBMCarticleIschemia/reperfusionCaspase-4 inflammasomePyroptosisBeclin1MedicineRCytologyQH573-671ENCell Communication and Signaling, Vol 19, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Ischemia/reperfusion Caspase-4 inflammasome Pyroptosis Beclin1 Medicine R Cytology QH573-671
spellingShingle	Ischemia/reperfusion Caspase-4 inflammasome Pyroptosis Beclin1 Medicine R Cytology QH573-671 Wenjing Sun Hongquan Lu Shujuan Dong Rui Li Yingjie Chu Nan Wang Yu Zhao Yabin Zhang Limeiting Wang Lin Sun Di Lu Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury
description	Abstract Background Myocardial reperfusion injury is often accompanied by cell death and inflammatory reactions. Recently, pyroptosis is gradually recognized as pivotal role in cardiovascular disease. However, little is known about the regulatory role of beclin1 in the control of caspase-4 activation and pyroptosis. The present study confirmed whether beclin1 regulates caspase-4 mediated pyroptosis and thereby protects Human Cardiac microvascular endothelial cells (HCMECs) against injury. Methods TTC and Evan's blue dye, western blot, immunofluorescence and immunohistochemistry staining were performed in wild mice and transgenic mice with overexpression of beclin 1(BECN1-Tg). CMECs were transfected with a beclin1 lentivirus. The cell cytotoxicity was analyzed by LDH-Cytotoxicity Assay Kit. The protein levels of autophagy protein (Beclin1, p62 and LC3II/LC3I) and caspase-4/GSDMD pathway were determined by western blot. Autophagic vacuoles in cells were monitored with RFP-GFP-LC3 using fluorescence microscope. Results I/R caused caspase-4 activity and gasdermin D expression increase in vivo and in vitro. Overexpression of beclin1 in heart tissue and CMECs suppressed the caspase-4 activity and decreased the levels of gasdermin D; meanwhile beclin1 overexpression also reduced IL-1β levels, promoted autophagy (p62 expression was inhibited while LC3II expression was increased) in the heart and CMECs. Interestingly, beclin1 overexpression increased animal survival and attenuated myocardial infarct size (45 ± 6.13 vs 22 ± 4.37), no-reflow area (39 ± 5.22 vs 16 ± 2.54) post-myocardial ischemia reperfusion. Conclusions Induction of beclin-1 signaling can be a potential therapeutic target in myocardial reperfusion-induced microvascular injury. Video Abstract
format	article
author	Wenjing Sun Hongquan Lu Shujuan Dong Rui Li Yingjie Chu Nan Wang Yu Zhao Yabin Zhang Limeiting Wang Lin Sun Di Lu
author_facet	Wenjing Sun Hongquan Lu Shujuan Dong Rui Li Yingjie Chu Nan Wang Yu Zhao Yabin Zhang Limeiting Wang Lin Sun Di Lu
author_sort	Wenjing Sun
title	Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury
title_short	Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury
title_full	Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury
title_fullStr	Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury
title_full_unstemmed	Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury
title_sort	beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury
publisher	BMC
publishDate	2021
url	https://doaj.org/article/7667ec6a30c6436e9ff57fda2deb58f7
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Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury

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