Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration
Pulmonary arterial hypertension (PAH) is a complex degenerative disorder marked by aberrant vascular remodeling associated with hyperproliferation and migration of endothelial cells (ECs). Previous reports implicated bone morphogenetic protein antagonist Gremlin 1 in this process; however, little is...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2019-04-01
|
Series: | Redox Biology |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231718308929 |
id |
doaj-03a0a00b4a084e85bcad0f2982a7abc7 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Daniel S. de Jesus Evan DeVallance Yao Li Micol Falabella Danielle Guimaraes Sruti Shiva Brett A. Kaufman Mark T. Gladwin Patrick J. Pagano |
spellingShingle |
Daniel S. de Jesus Evan DeVallance Yao Li Micol Falabella Danielle Guimaraes Sruti Shiva Brett A. Kaufman Mark T. Gladwin Patrick J. Pagano Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration Redox Biology |
author_facet |
Daniel S. de Jesus Evan DeVallance Yao Li Micol Falabella Danielle Guimaraes Sruti Shiva Brett A. Kaufman Mark T. Gladwin Patrick J. Pagano |
author_sort |
Daniel S. de Jesus |
title |
Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration |
title_short |
Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration |
title_full |
Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration |
title_fullStr |
Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration |
title_full_unstemmed |
Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration |
title_sort |
nox1/ref-1-mediated activation of creb promotes gremlin1-driven endothelial cell proliferation and migration |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2019-04-01 |
description |
Pulmonary arterial hypertension (PAH) is a complex degenerative disorder marked by aberrant vascular remodeling associated with hyperproliferation and migration of endothelial cells (ECs). Previous reports implicated bone morphogenetic protein antagonist Gremlin 1 in this process; however, little is known of the molecular mechanisms involved. The current study was designed to test whether redox signaling initiated by NADPH oxidase 1 (Nox1) could promote transcription factor CREB activation by redox factor 1 (Ref-1), transactivation of Gremlin1 transcription, EC migration, and proliferation. Human pulmonary arterial EC (HPAECs) exposed in vitro to hypoxia to recapitulate PAH signaling displayed induced Nox1 expression, reactive oxygen species (ROS) production, PKA activity, CREB phosphorylation, and CREB:CRE motif binding. These responses were abrogated by selective Nox1 inhibitor NoxA1ds and/or siRNA Nox1. Nox1-activated CREB migrated to the nucleus and bound to Ref-1 leading to CREB:CRE binding and Gremlin1 transcription. CHiP assay and CREB gene-silencing illustrated that CREB is pivotal for hypoxia-induced Gremlin1, which, in turn, stimulates EC proliferation and migration. In vivo, participation of Nox1, CREB, and Gremlin1, as well as CREB:CRE binding was corroborated in a rat PAH model. Activation of a previously unidentified Nox1-PKA-CREB/Ref-1 signaling pathway in pulmonary endothelial cells leads to Gremlin1 transactivation, proliferation and migration. These findings reveal a new signaling pathway by which Nox1 via induction of CREB and Gremlin1 signaling contributes to vascular remodeling and provide preclinical indication of its significance in PAH. Keywords: Nox1, CREB, Proliferation, Gremlin1, Ref-1, Migration |
url |
http://www.sciencedirect.com/science/article/pii/S2213231718308929 |
work_keys_str_mv |
AT danielsdejesus nox1ref1mediatedactivationofcrebpromotesgremlin1drivenendothelialcellproliferationandmigration AT evandevallance nox1ref1mediatedactivationofcrebpromotesgremlin1drivenendothelialcellproliferationandmigration AT yaoli nox1ref1mediatedactivationofcrebpromotesgremlin1drivenendothelialcellproliferationandmigration AT micolfalabella nox1ref1mediatedactivationofcrebpromotesgremlin1drivenendothelialcellproliferationandmigration AT danielleguimaraes nox1ref1mediatedactivationofcrebpromotesgremlin1drivenendothelialcellproliferationandmigration AT srutishiva nox1ref1mediatedactivationofcrebpromotesgremlin1drivenendothelialcellproliferationandmigration AT brettakaufman nox1ref1mediatedactivationofcrebpromotesgremlin1drivenendothelialcellproliferationandmigration AT marktgladwin nox1ref1mediatedactivationofcrebpromotesgremlin1drivenendothelialcellproliferationandmigration AT patrickjpagano nox1ref1mediatedactivationofcrebpromotesgremlin1drivenendothelialcellproliferationandmigration |
_version_ |
1725010171781971968 |
spelling |
doaj-03a0a00b4a084e85bcad0f2982a7abc72020-11-25T01:48:46ZengElsevierRedox Biology2213-23172019-04-0122Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migrationDaniel S. de Jesus0Evan DeVallance1Yao Li2Micol Falabella3Danielle Guimaraes4Sruti Shiva5Brett A. Kaufman6Mark T. Gladwin7Patrick J. Pagano8Vascular Medicine Institute, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United StatesVascular Medicine Institute, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United StatesVascular Medicine Institute, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United StatesVascular Medicine Institute, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States; Department of Medicine, University of Pittsburgh, 200 Lothrop St., Pittsburgh PA 15261, United StatesVascular Medicine Institute, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States; Department of Medicine, University of Pittsburgh, 200 Lothrop St., Pittsburgh PA 15261, United StatesVascular Medicine Institute, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States; Department of Medicine, University of Pittsburgh, 200 Lothrop St., Pittsburgh PA 15261, United StatesVascular Medicine Institute, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States; Department of Medicine, University of Pittsburgh, 200 Lothrop St., Pittsburgh PA 15261, United StatesDepartment of Medicine, University of Pittsburgh, 200 Lothrop St., Pittsburgh PA 15261, United StatesVascular Medicine Institute, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States; Correspondence to: Vascular Medicine Institute, Department of Pharmacology and Chemical Biology, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261, United States.Pulmonary arterial hypertension (PAH) is a complex degenerative disorder marked by aberrant vascular remodeling associated with hyperproliferation and migration of endothelial cells (ECs). Previous reports implicated bone morphogenetic protein antagonist Gremlin 1 in this process; however, little is known of the molecular mechanisms involved. The current study was designed to test whether redox signaling initiated by NADPH oxidase 1 (Nox1) could promote transcription factor CREB activation by redox factor 1 (Ref-1), transactivation of Gremlin1 transcription, EC migration, and proliferation. Human pulmonary arterial EC (HPAECs) exposed in vitro to hypoxia to recapitulate PAH signaling displayed induced Nox1 expression, reactive oxygen species (ROS) production, PKA activity, CREB phosphorylation, and CREB:CRE motif binding. These responses were abrogated by selective Nox1 inhibitor NoxA1ds and/or siRNA Nox1. Nox1-activated CREB migrated to the nucleus and bound to Ref-1 leading to CREB:CRE binding and Gremlin1 transcription. CHiP assay and CREB gene-silencing illustrated that CREB is pivotal for hypoxia-induced Gremlin1, which, in turn, stimulates EC proliferation and migration. In vivo, participation of Nox1, CREB, and Gremlin1, as well as CREB:CRE binding was corroborated in a rat PAH model. Activation of a previously unidentified Nox1-PKA-CREB/Ref-1 signaling pathway in pulmonary endothelial cells leads to Gremlin1 transactivation, proliferation and migration. These findings reveal a new signaling pathway by which Nox1 via induction of CREB and Gremlin1 signaling contributes to vascular remodeling and provide preclinical indication of its significance in PAH. Keywords: Nox1, CREB, Proliferation, Gremlin1, Ref-1, Migrationhttp://www.sciencedirect.com/science/article/pii/S2213231718308929 |