Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3

Abstract Background Diabetes mellitus (DM), a most common chronic disease, is featured with impaired endothelial function and bioavailability of nitric oxide (NO), while E3 ubiquitin ligase appears to alleviate endothelial dysfunction as a promising option for DM treatment. Herein, we aimed to deter...

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Autores principales:	Qingsong Jin, Liangyan Lin, Tiantian Zhao, Xiaoyan Yao, Yaqin Teng, Dongdong Zhang, Yongjun Jin, Meizi Yang
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Diabetes mellitus Cbl Endothelial dysfunction JAK2 STAT4 Human umbilical vein endothelial cells Medicine R
Acceso en línea:	https://doaj.org/article/066e7511a6b149e18eaa94dde577c516
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spelling	oai:doaj.org-article:066e7511a6b149e18eaa94dde577c5162021-11-21T12:05:01ZOverexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me310.1186/s12967-021-03069-w1479-5876https://doaj.org/article/066e7511a6b149e18eaa94dde577c5162021-11-01T00:00:00Zhttps://doi.org/10.1186/s12967-021-03069-whttps://doaj.org/toc/1479-5876Abstract Background Diabetes mellitus (DM), a most common chronic disease, is featured with impaired endothelial function and bioavailability of nitric oxide (NO), while E3 ubiquitin ligase appears to alleviate endothelial dysfunction as a promising option for DM treatment. Herein, we aimed to determine whether E3 ubiquitin ligase casitas B-lineage lymphoma (Cbl) alleviates endothelial dysfunction in DM rats by JAK2/STAT4 pathway. Methods A rat model of DM was developed through intraperitoneal injection of streptozotocin, followed by collection of aortic tissues to determine the expression of Cbl, JAK2, runt-related transcription factor 3 (Runx3) and STAT4. Human umbilical vein endothelial cells (HUVECs) were cultured in high glucose (HG) condition to induce DM as an in vitro model. With gain- and loss-function method, we assessed the aberrantly expressed Cb1 on endothelial dysfunction, NO production and apoptosis of HUVECs. Results Cbl was reduced in DM rat tissues and HG-induced HUVECs, where JAK2, Runx3 and STAT4 were elevated. It was found that overexpression of Cbl alleviated endothelial dysfunction by increasing NO production and restoring vasodilation and suppressing apoptosis of HUVECs. Mechanistically, Cb1 enhanced JAK2 ubiquitination and decreased JAK2 and STAT4 expression, where STAT4 improved Runx3 expression by regulating histone H3 lysine 4 trimethylation level. Overexpression of JAK2 and STAT4, or Runx3 increased apoptosis of HUVECs, abrogating the effect of Cb1 on endothelial function. Conclusion In conclusion, Cbl alleviates endothelial dysfunction by inactivation of the JAK2/STAT4 pathway and inhibition of Runx3 expression in DM. These evidence might underlie novel Cbl-based treatment against DM in the future.Qingsong JinLiangyan LinTiantian ZhaoXiaoyan YaoYaqin TengDongdong ZhangYongjun JinMeizi YangBMCarticleDiabetes mellitusCblEndothelial dysfunctionJAK2STAT4Human umbilical vein endothelial cellsMedicineRENJournal of Translational Medicine, Vol 19, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diabetes mellitus Cbl Endothelial dysfunction JAK2 STAT4 Human umbilical vein endothelial cells Medicine R
spellingShingle	Diabetes mellitus Cbl Endothelial dysfunction JAK2 STAT4 Human umbilical vein endothelial cells Medicine R Qingsong Jin Liangyan Lin Tiantian Zhao Xiaoyan Yao Yaqin Teng Dongdong Zhang Yongjun Jin Meizi Yang Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3
description	Abstract Background Diabetes mellitus (DM), a most common chronic disease, is featured with impaired endothelial function and bioavailability of nitric oxide (NO), while E3 ubiquitin ligase appears to alleviate endothelial dysfunction as a promising option for DM treatment. Herein, we aimed to determine whether E3 ubiquitin ligase casitas B-lineage lymphoma (Cbl) alleviates endothelial dysfunction in DM rats by JAK2/STAT4 pathway. Methods A rat model of DM was developed through intraperitoneal injection of streptozotocin, followed by collection of aortic tissues to determine the expression of Cbl, JAK2, runt-related transcription factor 3 (Runx3) and STAT4. Human umbilical vein endothelial cells (HUVECs) were cultured in high glucose (HG) condition to induce DM as an in vitro model. With gain- and loss-function method, we assessed the aberrantly expressed Cb1 on endothelial dysfunction, NO production and apoptosis of HUVECs. Results Cbl was reduced in DM rat tissues and HG-induced HUVECs, where JAK2, Runx3 and STAT4 were elevated. It was found that overexpression of Cbl alleviated endothelial dysfunction by increasing NO production and restoring vasodilation and suppressing apoptosis of HUVECs. Mechanistically, Cb1 enhanced JAK2 ubiquitination and decreased JAK2 and STAT4 expression, where STAT4 improved Runx3 expression by regulating histone H3 lysine 4 trimethylation level. Overexpression of JAK2 and STAT4, or Runx3 increased apoptosis of HUVECs, abrogating the effect of Cb1 on endothelial function. Conclusion In conclusion, Cbl alleviates endothelial dysfunction by inactivation of the JAK2/STAT4 pathway and inhibition of Runx3 expression in DM. These evidence might underlie novel Cbl-based treatment against DM in the future.
format	article
author	Qingsong Jin Liangyan Lin Tiantian Zhao Xiaoyan Yao Yaqin Teng Dongdong Zhang Yongjun Jin Meizi Yang
author_facet	Qingsong Jin Liangyan Lin Tiantian Zhao Xiaoyan Yao Yaqin Teng Dongdong Zhang Yongjun Jin Meizi Yang
author_sort	Qingsong Jin
title	Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3
title_short	Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3
title_full	Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3
title_fullStr	Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3
title_full_unstemmed	Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3
title_sort	overexpression of e3 ubiquitin ligase cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the jak2/stat4 signaling and runx3-mediated h3k4me3
publisher	BMC
publishDate	2021
url	https://doaj.org/article/066e7511a6b149e18eaa94dde577c516
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Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3

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