Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration.

Redox Biology
Daniel S de JesusPatrick J Pagano

Abstract

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,...Continue Reading

Citations

Jul 7, 2019·International Journal of Molecular Sciences·Koh Nakayama, Naoyuki Kataoka
Aug 5, 2020·Journal of the American Heart Association·Liukun MengXiaoyan Liu
Aug 12, 2020·Journal of Cellular Physiology·Zi-Ming LiCha-Xiang Guan
Dec 13, 2019·Antioxidants & Redox Signaling·Mathieu Chocry, Ludovic Leloup
Oct 1, 2020·Clinical and Translational Medicine·Tao XuShuangyue Liu
Aug 14, 2019·Current Opinion in Physiology·Zdravka DanevaSwapnil K Sonkusare
Aug 5, 2020·Antioxidants & Redox Signaling·Anastasia GorelovaImad Al Ghouleh
Apr 22, 2021·Proceedings of the National Academy of Sciences of the United States of America·Zdravka DanevaSwapnil K Sonkusare
Jun 3, 2021·Antioxidants·Daria S Kostyunina, Paul McLoughlin

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Methods Mentioned

BETA
ELISA
immunoprecipitation
Infrared Imaging
flow cytometry
pulldown
PCR
electrophoresis
co-immunoprecipitation
immunoprecipitation assay
transfection

Software Mentioned

GraphPad
ImageJ
FlowJo
geneXplain
GraphPad Prism
geneXplain platform
Image J

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