Dataset Information

Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1.

ABSTRACT: Angiogenic factor with G-patch and FHA domains 1 (AGGF1) is involved in vascular development, angiogenesis, specification of hemangioblasts, and differentiation of veins. When mutated, however, it causes Klippel-Trenaunay syndrome, a vascular disorder. In this study, we show that angiotensin II (AngII)-the major effector of the renin-angiotensin system and one of the most important regulators of the cardiovascular system-induces the expression of AGGF1 through NF-κB, and that AGGF1 plays a key role in AngII-induced angiogenesis. AngII significantly up-regulated the levels of AGGF1 mRNA and protein in HUVECs at concentrations of 10-40 μg/ml but not >60 μg/ml. AngII type 1 receptor (AT1R) inhibitor losartan inhibited AngII-induced up-regulation of AGGF1, whereas AT2R inhibitor PD123319 further increased AngII-induced up-regulation of AGGF1. Up-regulation of AGGF1 by AngII was blocked by NF-κB inhibitors, and p65 binds directly to a binding site at the promoter/regulatory region of AGGF1 and transcriptionally activates AGGF1 expression. AngII-induced endothelial tube formation was blocked by small interfering RNAs (siRNAs) for RELA (RELA proto-oncogene, NF-κB subunit)/p65 or AGGF1, and the effect of RELA siRNA was rescued by AGGF1. AngII-induced angiogenesis from aortic rings was severely impaired in Aggf1^+/- mice, and the effect was restored by AGGF1. These data suggest that AngII acts as a critical regulator of AGGF1 expression through NF-κB, and that AGGF1 plays a key role in AngII-induced angiogenesis.-Si, W., Xie, W., Deng, W., Xiao, Y., Karnik, S. S., Xu, C., Chen, Q., Wang, Q. K. Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1.

SUBMITTER: Si W

PROVIDER: S-EPMC6103173 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1.

Si Wenxia W Xie Wen W Deng Wenbing W Xiao Yi Y Karnik Sadashiva S SS Xu Chengqi C Chen Qiuyun Q Wang Qing Kenneth QK

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20180411 9

Angiogenic factor with G-patch and FHA domains 1 (AGGF1) is involved in vascular development, angiogenesis, specification of hemangioblasts, and differentiation of veins. When mutated, however, it causes Klippel-Trenaunay syndrome, a vascular disorder. In this study, we show that angiotensin II (AngII)-the major effector of the renin-angiotensin system and one of the most important regulators of the cardiovascular system-induces the expression of AGGF1 through NF-κB, and that AGGF1 plays a key r ...[more]

PMID: 29641288

Similar Datasets

Project description:Orientia tsutsugamushi causes scrub typhus, a potentially fatal infection that threatens over one billion people. Nuclear translocation of the transcription factor, NF-κB, is the central initiating cellular event in the antimicrobial response. Here, we report that NF-κB p65 nuclear accumulation and NF-κB-dependent transcription are inhibited in O. tsutsugamushi infected HeLa cells and/or primary macrophages, even in the presence of TNFα. The bacterium modulates p65 subcellular localization by neither degrading it nor inhibiting IκBα degradation. Rather, it exploits host exportin 1 to mediate p65 nuclear export, as this phenomenon is leptomycin B-sensitive. O. tsutsugamushi antagonizes NF-κB-activated transcription even when exportin 1 is inhibited and NF-κB consequently remains in the nucleus. Two ankyrin repeat-containing effectors (Anks), Ank1 and Ank6, each of which possess a C-terminal F-box and exhibit 58.5% amino acid identity, are linked to the pathogen's ability to modulate NF-κB. When ectopically expressed, both translocate to the nucleus, abrogate NF-κB-activated transcription in an exportin 1-independent manner, and pronouncedly reduce TNFα-induced p65 nuclear levels by exportin 1-dependent means. Flag-tagged Ank 1 and Ank6 co-immunoprecipitate p65 and exportin 1. Both also bind importin β1, a host protein that is essential for the classical nuclear import pathway. Importazole, which blocks importin β1 activity, abrogates Ank1 and Ank6 nuclear translocation. The Ank1 and Ank6 regions that bind importin β1 also mediate their transport into the nucleus. Yet, these regions are distinct from those that bind p65/exportin 1. The Ank1 and Ank6 F-box and the region that lies between it and the ankyrin repeat domain are essential for blocking p65 nuclear accumulation. These data reveal a novel mechanism by which O. tsutsugamushi modulates the activity and nuclear transport of NF-κB p65 and identify the first microbial proteins that co-opt both importin β1 and exportin 1 to antagonize a critical arm of the antimicrobial response.

Project description:BackgroundNeuroinflammation and blood-brain barrier (BBB) disruption are two critical mechanisms of subarachnoid hemorrhage (SAH)-induced brain injury, which are closely related to patient prognosis. Recently, angiogenic factor with G-patch and FHA domain 1 (Aggf1) was shown to inhibit inflammatory effect and preserve vascular integrity in non-nervous system diseases. This study aimed to determine whether Aggf1 could attenuate neuroinflammation and preserve BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective roles.MethodsTwo hundred forty-nine male Sprague-Dawley rats were subjected to the endovascular perforation model of SAH. Recombinant human Aggf1 (rh-Aggf1) was administered intravenously via tail vein injection at 1 h after SAH induction. To investigate the underlying neuroprotection mechanism, Aggf1 small interfering RNA (Aggf1 siRNA) and PI3K-specific inhibitor LY294002 were administered through intracerebroventricular (i.c.v.) before SAH induction. SAH grade, neurological score, brain water content, BBB permeability, Western blot, and immunohistochemistry were performed.ResultsExpression of endogenous Aggf1 was markedly increased after SAH. Aggf1 was primarily expressed in endothelial cells and astrocytes, as well as microglia after SAH. Administration of rh-Aggf1 significantly reduced brain water content and BBB permeability, decreased the numbers of infiltrating neutrophils, and activated microglia in the ipsilateral cerebral cortex following SAH. Furthermore, rh-Aggf1 treatment improved both short- and long-term neurological functions after SAH. Meanwhile, exogenous rh-Aggf1 significantly increased the expression of PI3K, p-Akt, VE-cadherin, Occludin, and Claudin-5, as well as decreased the expression of p-NF-κB p65, albumin, myeloperoxidase (MPO), TNF-α, and IL-1β. Conversely, knockdown of endogenous Aggf1 aggravated BBB breakdown, inflammatory response and neurological impairments at 24 h after SAH. Additionally, the protective roles of rh-Aggf1 were abolished by LY294002.ConclusionsTaken together, exogenous Aggf1 treatment attenuated neuroinflammation and BBB disruption, improved neurological deficits after SAH in rats, at least in part through the PI3K/Akt/NF-κB pathway.

Dataset Information

Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1.

Publications

Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets