Cargando…

NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria

Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are the major enzymatic source of reactive oxygen species (ROS). NOX2 and NOX4 are expressed in the heart but its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion is unclear. This study investigated the effect of NOX on AN...

Descripción completa

Detalles Bibliográficos
Autores principales: Wu, Cheng-zhe, Li, Xiang, Hong, Lan, Han, Zhuo-na, Liu, Ying, Wei, Cheng-xi, Cui, Xun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Korean Physiological Society and The Korean Society of Pharmacology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893495/
https://www.ncbi.nlm.nih.gov/pubmed/33602886
http://dx.doi.org/10.4196/kjpp.2021.25.2.159
_version_ 1783653062665043968
author Wu, Cheng-zhe
Li, Xiang
Hong, Lan
Han, Zhuo-na
Liu, Ying
Wei, Cheng-xi
Cui, Xun
author_facet Wu, Cheng-zhe
Li, Xiang
Hong, Lan
Han, Zhuo-na
Liu, Ying
Wei, Cheng-xi
Cui, Xun
author_sort Wu, Cheng-zhe
collection PubMed
description Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are the major enzymatic source of reactive oxygen species (ROS). NOX2 and NOX4 are expressed in the heart but its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion is unclear. This study investigated the effect of NOX on ANP secretion induced by hypoxia in isolated beating rat atria. The results showed that hypoxia significantly upregulated NOX4 but not NOX2 expression, which was completely abolished by endothelin-1 (ET-1) type A and B receptor antagonists BQ123 (0.3 µM) and BQ788 (0.3 µM). ET-1-upregulated NOX4 expression was also blocked by antagonists of secreted phospholipase A2 (sPLA2; varespladib, 5.0 µM) and cytosolic PLA2 (cPLA2; CAY10650, 120.0 nM), and ET-1-induced cPLA2 expression was inhibited by varespladib under normoxia. Moreover, hypoxia-increased ANP secretion was evidently attenuated by the NOX4 antagonist GLX351322 (35.0 µM) and inhibitor of ROS N-Acetyl-D-cysteine (NAC, 15.0 mM), and hypoxia-increased production of ROS was blocked by GLX351322. In addition, hypoxia markedly upregulated Src expression, which was blocked by ET receptors, NOX4, and ROS antagonists. ET-1-increased Src expression was also inhibited by NAC under normoxia. Furthermore, hypoxia-activated extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) were completely abolished by Src inhibitor 1 (1.0 µM), and hypoxia-increased GATA4 was inhibited by the ERK1/2 and Akt antagonists PD98059 (10.0 µM) and LY294002 (10.0 µM), respectively. However, hypoxia-induced ANP secretion was substantially inhibited by Src inhibitor. These results indicate that NOX4/Src modulated by ET-1 regulates ANP secretion by activating ERK1/2 and Akt/GATA4 signaling in isolated beating rat hypoxic atria.
format Online
Article
Text
id pubmed-7893495
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher The Korean Physiological Society and The Korean Society of Pharmacology
record_format MEDLINE/PubMed
spelling pubmed-78934952021-03-01 NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria Wu, Cheng-zhe Li, Xiang Hong, Lan Han, Zhuo-na Liu, Ying Wei, Cheng-xi Cui, Xun Korean J Physiol Pharmacol Original Article Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are the major enzymatic source of reactive oxygen species (ROS). NOX2 and NOX4 are expressed in the heart but its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion is unclear. This study investigated the effect of NOX on ANP secretion induced by hypoxia in isolated beating rat atria. The results showed that hypoxia significantly upregulated NOX4 but not NOX2 expression, which was completely abolished by endothelin-1 (ET-1) type A and B receptor antagonists BQ123 (0.3 µM) and BQ788 (0.3 µM). ET-1-upregulated NOX4 expression was also blocked by antagonists of secreted phospholipase A2 (sPLA2; varespladib, 5.0 µM) and cytosolic PLA2 (cPLA2; CAY10650, 120.0 nM), and ET-1-induced cPLA2 expression was inhibited by varespladib under normoxia. Moreover, hypoxia-increased ANP secretion was evidently attenuated by the NOX4 antagonist GLX351322 (35.0 µM) and inhibitor of ROS N-Acetyl-D-cysteine (NAC, 15.0 mM), and hypoxia-increased production of ROS was blocked by GLX351322. In addition, hypoxia markedly upregulated Src expression, which was blocked by ET receptors, NOX4, and ROS antagonists. ET-1-increased Src expression was also inhibited by NAC under normoxia. Furthermore, hypoxia-activated extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) were completely abolished by Src inhibitor 1 (1.0 µM), and hypoxia-increased GATA4 was inhibited by the ERK1/2 and Akt antagonists PD98059 (10.0 µM) and LY294002 (10.0 µM), respectively. However, hypoxia-induced ANP secretion was substantially inhibited by Src inhibitor. These results indicate that NOX4/Src modulated by ET-1 regulates ANP secretion by activating ERK1/2 and Akt/GATA4 signaling in isolated beating rat hypoxic atria. The Korean Physiological Society and The Korean Society of Pharmacology 2021-03-01 2021-03-01 /pmc/articles/PMC7893495/ /pubmed/33602886 http://dx.doi.org/10.4196/kjpp.2021.25.2.159 Text en Copyright © Korean J Physiol Pharmacol This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Wu, Cheng-zhe
Li, Xiang
Hong, Lan
Han, Zhuo-na
Liu, Ying
Wei, Cheng-xi
Cui, Xun
NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria
title NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria
title_full NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria
title_fullStr NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria
title_full_unstemmed NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria
title_short NOX4/Src regulates ANP secretion through activating ERK1/2 and Akt/GATA4 signaling in beating rat hypoxic atria
title_sort nox4/src regulates anp secretion through activating erk1/2 and akt/gata4 signaling in beating rat hypoxic atria
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893495/
https://www.ncbi.nlm.nih.gov/pubmed/33602886
http://dx.doi.org/10.4196/kjpp.2021.25.2.159
work_keys_str_mv AT wuchengzhe nox4srcregulatesanpsecretionthroughactivatingerk12andaktgata4signalinginbeatingrathypoxicatria
AT lixiang nox4srcregulatesanpsecretionthroughactivatingerk12andaktgata4signalinginbeatingrathypoxicatria
AT honglan nox4srcregulatesanpsecretionthroughactivatingerk12andaktgata4signalinginbeatingrathypoxicatria
AT hanzhuona nox4srcregulatesanpsecretionthroughactivatingerk12andaktgata4signalinginbeatingrathypoxicatria
AT liuying nox4srcregulatesanpsecretionthroughactivatingerk12andaktgata4signalinginbeatingrathypoxicatria
AT weichengxi nox4srcregulatesanpsecretionthroughactivatingerk12andaktgata4signalinginbeatingrathypoxicatria
AT cuixun nox4srcregulatesanpsecretionthroughactivatingerk12andaktgata4signalinginbeatingrathypoxicatria