Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway

Hyperhomocysteinemia is a well-recognized independent risk factor for cardiovascular disease. To date, the mechanism of pathological plasma homocysteine (Hcy) level elevation remains to be elucidated. We aimed to investigate the levels of progranulin (PGRN), Eph-receptor tyrosine kinase-type A2 (Eph...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Dan Tian, Qing Qin, Mingfei Li, Xiaoyu Li, Qing Xu, Qianzhou Lv
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	progranulin EphA2 hyperhomocysteinemia adhesion VE-Cadherin Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/ce74aec2fdb74bf69011df5ed52fe1ab
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ce74aec2fdb74bf69011df5ed52fe1ab
record_format	dspace
spelling	oai:doaj.org-article:ce74aec2fdb74bf69011df5ed52fe1ab2021-11-05T16:48:39ZHomocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway1663-981210.3389/fphar.2020.614760https://doaj.org/article/ce74aec2fdb74bf69011df5ed52fe1ab2021-01-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2020.614760/fullhttps://doaj.org/toc/1663-9812Hyperhomocysteinemia is a well-recognized independent risk factor for cardiovascular disease. To date, the mechanism of pathological plasma homocysteine (Hcy) level elevation remains to be elucidated. We aimed to investigate the levels of progranulin (PGRN), Eph-receptor tyrosine kinase-type A2 (EphA2), vascular cell adhesion molecule-1 (VCAM-1), and Hcy in patients with arteriosclerosis and investigate their functions in Hcy-injured human umbilical vein endothelial cells (HUVECs). EphA2 knockdown was induced in HUVECs by shRNA lentivirus infection with EphA2-RNAi, and bulk RNA-seq assay was performed. Then we investigated the mechanism underlying the effect of recombinant human PGRN (rhPGRN) combined with shRNA interference of EphA2 on cell proliferation, migration, and angiogenesis in Hcy-injured HUVECs. Results showed that serum EphA2, VCAM-1, and Hcy levels in acute coronary syndrome patients were significantly higher than those in chronic coronary syndrome patients (p = 0.000; p = 0.000; p = 0.033, respectively). In vitro, we demonstrated that knockdown of EphA2 significantly impaired cell adhesion and inhibited HUVECs migration and angiogenesis (p < 0.001), which was associated with reduction in VCAM1 and VE-cadherin (p < 0.05). Hcy modulated the expression of PGRN and EphA2 in a time-and dose-dependent manner. However, rhPGRN ameliorated the Hcy-induced reduction in cell viability and migration (p < 0.05). Mechanistically, we found that PGRN/EphA2 and its downstream AKT/NF-κB signaling might be the primary signal transduction pathways underlying Hcy-induced injury. The present study illustrated that PGRN plays a previously unrecognized role in Hcy-induced endothelial injury, which is achieved through its interaction with EphA2 signaling, implying a promising therapeutic target for cardiovascular disease.Dan TianQing QinMingfei LiXiaoyu LiQing XuQianzhou LvFrontiers Media S.A.articleprogranulinEphA2hyperhomocysteinemiaadhesionVE-CadherinTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	progranulin EphA2 hyperhomocysteinemia adhesion VE-Cadherin Therapeutics. Pharmacology RM1-950
spellingShingle	progranulin EphA2 hyperhomocysteinemia adhesion VE-Cadherin Therapeutics. Pharmacology RM1-950 Dan Tian Qing Qin Mingfei Li Xiaoyu Li Qing Xu Qianzhou Lv Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway
description	Hyperhomocysteinemia is a well-recognized independent risk factor for cardiovascular disease. To date, the mechanism of pathological plasma homocysteine (Hcy) level elevation remains to be elucidated. We aimed to investigate the levels of progranulin (PGRN), Eph-receptor tyrosine kinase-type A2 (EphA2), vascular cell adhesion molecule-1 (VCAM-1), and Hcy in patients with arteriosclerosis and investigate their functions in Hcy-injured human umbilical vein endothelial cells (HUVECs). EphA2 knockdown was induced in HUVECs by shRNA lentivirus infection with EphA2-RNAi, and bulk RNA-seq assay was performed. Then we investigated the mechanism underlying the effect of recombinant human PGRN (rhPGRN) combined with shRNA interference of EphA2 on cell proliferation, migration, and angiogenesis in Hcy-injured HUVECs. Results showed that serum EphA2, VCAM-1, and Hcy levels in acute coronary syndrome patients were significantly higher than those in chronic coronary syndrome patients (p = 0.000; p = 0.000; p = 0.033, respectively). In vitro, we demonstrated that knockdown of EphA2 significantly impaired cell adhesion and inhibited HUVECs migration and angiogenesis (p < 0.001), which was associated with reduction in VCAM1 and VE-cadherin (p < 0.05). Hcy modulated the expression of PGRN and EphA2 in a time-and dose-dependent manner. However, rhPGRN ameliorated the Hcy-induced reduction in cell viability and migration (p < 0.05). Mechanistically, we found that PGRN/EphA2 and its downstream AKT/NF-κB signaling might be the primary signal transduction pathways underlying Hcy-induced injury. The present study illustrated that PGRN plays a previously unrecognized role in Hcy-induced endothelial injury, which is achieved through its interaction with EphA2 signaling, implying a promising therapeutic target for cardiovascular disease.
format	article
author	Dan Tian Qing Qin Mingfei Li Xiaoyu Li Qing Xu Qianzhou Lv
author_facet	Dan Tian Qing Qin Mingfei Li Xiaoyu Li Qing Xu Qianzhou Lv
author_sort	Dan Tian
title	Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway
title_short	Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway
title_full	Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway
title_fullStr	Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway
title_full_unstemmed	Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway
title_sort	homocysteine impairs endothelial cell barrier function and angiogenic potential via the progranulin/epha2 pathway
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/ce74aec2fdb74bf69011df5ed52fe1ab
work_keys_str_mv	AT dantian homocysteineimpairsendothelialcellbarrierfunctionandangiogenicpotentialviatheprogranulinepha2pathway AT qingqin homocysteineimpairsendothelialcellbarrierfunctionandangiogenicpotentialviatheprogranulinepha2pathway AT mingfeili homocysteineimpairsendothelialcellbarrierfunctionandangiogenicpotentialviatheprogranulinepha2pathway AT xiaoyuli homocysteineimpairsendothelialcellbarrierfunctionandangiogenicpotentialviatheprogranulinepha2pathway AT qingxu homocysteineimpairsendothelialcellbarrierfunctionandangiogenicpotentialviatheprogranulinepha2pathway AT qianzhoulv homocysteineimpairsendothelialcellbarrierfunctionandangiogenicpotentialviatheprogranulinepha2pathway
_version_	1718444127745474560

Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway

Ejemplares similares