Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice

Abstract Stress-induced alteration in endothelial cells (ECs) integrity precedes the development of atherosclerosis. Previous studies showed that the soluble recombinant thrombomodulin (rTM) not only increases ECs proliferation but also exerts anti-apoptotic activity in ECs. However, the functional...

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Autores principales:	Po-Sheng Chen, Kuan-Chieh Wang, Ting-Hsing Chao, Hsing-Chun Chung, Shi-Ya Tseng, Chawn-Yau Luo, Guey-Yueh Shi, Hua-Lin Wu, Yi-Heng Li
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8e8dabad06ad4d79a6b1dbca4e9c35df
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spelling	oai:doaj.org-article:8e8dabad06ad4d79a6b1dbca4e9c35df2021-12-02T15:06:16ZRecombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice10.1038/s41598-017-03443-z2045-2322https://doaj.org/article/8e8dabad06ad4d79a6b1dbca4e9c35df2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03443-zhttps://doaj.org/toc/2045-2322Abstract Stress-induced alteration in endothelial cells (ECs) integrity precedes the development of atherosclerosis. Previous studies showed that the soluble recombinant thrombomodulin (rTM) not only increases ECs proliferation but also exerts anti-apoptotic activity in ECs. However, the functional significance of soluble rTM on autophagy-related apoptosis in ECs is still undetermined. Implicating a cytoprotective role for rTM in persistent serum starvation (SS)-induced autophagy in cultured ECs, we found that treatment of rTM decreased the expression of SS-induced autophagy-related proteins, ATG5 and LC3, and the formation of autophagosomes through activation of AKT/mTOR pathway. In addition, treatment of rTM decreased SS-induced EC apoptosis, but this effect of rTM could not be recapitulated by co-treatment with a potent autophagy inducer, rapamycin and in ECs with ATG5 knockdown. In human atherosclerosis specimens, expression of autophagy markers, ATG13 and LC3, were more abundant in aortic intimal ECs with severe atherosclerosis than those without atherosclerosis. Moreover, compared to saline treatment group, administration of rTM reduced LC3 and ATG13 expression, intimal EC apoptosis, and atherosclerotic lesion severity in the aorta of apolipoprotein E deficient mice. In conclusion, treatment with rTM suppressed stress-induced autophagy overactivation in ECs, provided ECs protective effects, and decreased atherosclerosis in apolipoprotein E deficient mice.Po-Sheng ChenKuan-Chieh WangTing-Hsing ChaoHsing-Chun ChungShi-Ya TsengChawn-Yau LuoGuey-Yueh ShiHua-Lin WuYi-Heng LiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Po-Sheng Chen Kuan-Chieh Wang Ting-Hsing Chao Hsing-Chun Chung Shi-Ya Tseng Chawn-Yau Luo Guey-Yueh Shi Hua-Lin Wu Yi-Heng Li Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice
description	Abstract Stress-induced alteration in endothelial cells (ECs) integrity precedes the development of atherosclerosis. Previous studies showed that the soluble recombinant thrombomodulin (rTM) not only increases ECs proliferation but also exerts anti-apoptotic activity in ECs. However, the functional significance of soluble rTM on autophagy-related apoptosis in ECs is still undetermined. Implicating a cytoprotective role for rTM in persistent serum starvation (SS)-induced autophagy in cultured ECs, we found that treatment of rTM decreased the expression of SS-induced autophagy-related proteins, ATG5 and LC3, and the formation of autophagosomes through activation of AKT/mTOR pathway. In addition, treatment of rTM decreased SS-induced EC apoptosis, but this effect of rTM could not be recapitulated by co-treatment with a potent autophagy inducer, rapamycin and in ECs with ATG5 knockdown. In human atherosclerosis specimens, expression of autophagy markers, ATG13 and LC3, were more abundant in aortic intimal ECs with severe atherosclerosis than those without atherosclerosis. Moreover, compared to saline treatment group, administration of rTM reduced LC3 and ATG13 expression, intimal EC apoptosis, and atherosclerotic lesion severity in the aorta of apolipoprotein E deficient mice. In conclusion, treatment with rTM suppressed stress-induced autophagy overactivation in ECs, provided ECs protective effects, and decreased atherosclerosis in apolipoprotein E deficient mice.
format	article
author	Po-Sheng Chen Kuan-Chieh Wang Ting-Hsing Chao Hsing-Chun Chung Shi-Ya Tseng Chawn-Yau Luo Guey-Yueh Shi Hua-Lin Wu Yi-Heng Li
author_facet	Po-Sheng Chen Kuan-Chieh Wang Ting-Hsing Chao Hsing-Chun Chung Shi-Ya Tseng Chawn-Yau Luo Guey-Yueh Shi Hua-Lin Wu Yi-Heng Li
author_sort	Po-Sheng Chen
title	Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice
title_short	Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice
title_full	Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice
title_fullStr	Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice
title_full_unstemmed	Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice
title_sort	recombinant thrombomodulin exerts anti-autophagic action in endothelial cells and provides anti-atherosclerosis effect in apolipoprotein e deficient mice
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8e8dabad06ad4d79a6b1dbca4e9c35df
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Recombinant Thrombomodulin Exerts Anti-autophagic Action in Endothelial Cells and Provides Anti-atherosclerosis Effect in Apolipoprotein E Deficient Mice

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