Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.

<h4>Introduction</h4>Early allograft dysfunction following lung transplantation is mainly an ischemia/reperfusion (IR) injury. We showed that relaxin-2 (relaxin) exerts a protective effect in lung IR, attributable to decreases in endothelin-1 (ET-1) production, leukocyte recruitment, and...

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Autores principales:	Konstantin Alexiou, Manuel Wilbring, Klaus Matschke, Thomas Dschietzig
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4d1b84e7727d43b7a9d9c8ee62b8bf40
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spelling	oai:doaj.org-article:4d1b84e7727d43b7a9d9c8ee62b8bf402021-11-18T08:53:11ZRelaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.1932-620310.1371/journal.pone.0075592https://doaj.org/article/4d1b84e7727d43b7a9d9c8ee62b8bf402013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24098703/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Introduction</h4>Early allograft dysfunction following lung transplantation is mainly an ischemia/reperfusion (IR) injury. We showed that relaxin-2 (relaxin) exerts a protective effect in lung IR, attributable to decreases in endothelin-1 (ET-1) production, leukocyte recruitment, and free radical generation. Here, we summarize our investigations into relaxin's signalling.<h4>Materials and methods</h4>Isolated rat lungs were perfused with vehicle or 5 nM relaxin (n = 6-10 each). Thereafter, experiments were conducted in the presence of relaxin plus vehicle, the protein kinase A inhibitors H-89 and KT-5720, the NO synthase (NOS) inhibitor L-NAME, the iNOS inhibitor 1400W, the nNOS inhibitor SMTC, the extracellular signal-regulated kinase-1/2 (ERK-1/2) inhibitor PD-98059, the phosphatidylinositol-3 kinase (PI3K) inhibitor wortmannin, the endothelin type-B (ETB) antagonist A-192621, or the glucocorticoid receptor (GR) antagonist RU-486. After 90 min ischemia and 90 min reperfusion we determined wet-to-dry (W/D) weight ratio, mean pulmonary arterial pressure (MPAP), vascular release of ET-1, neutrophil elastase (NE), myeloperoxidase (MPO), and malondialdehyde (MDA). Primary rat pulmonary vascular cells were similarly treated.<h4>Results</h4>IR lungs displayed significantly elevated W/D ratios, MPAP, as well as ET-1, NE, MDA, and MPO. In the presence of relaxin, all of these parameters were markedly improved. This protective effect was completely abolished by L-NAME, 1400W, PD-98059, and wortmannin whereas neither PKA and nNOS inhibition nor ETB and GR antagonism were effective. Analysis of NOS gene expression and activity revealed that the relaxin-induced early and moderate iNOS stimulation is ERK-1/2-dependent and counter-balanced by PI3K. Relaxin-PI3K-related phosphorylation of a forkhead transcription factor, FKHRL1, paralleled this regulation. In pulmonary endothelial and smooth muscle cells, FKHRL1 was essential to relaxin-PI3K signalling towards iNOS.<h4>Conclusion</h4>In this short-time experimental setting, relaxin protects against IR-induced lung injury via early and moderate iNOS induction, dependent on balanced ERK-1/2 and PI3K-FKHRL1 stimulation. These findings render relaxin a candidate drug for lung preservation.Konstantin AlexiouManuel WilbringKlaus MatschkeThomas DschietzigPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e75592 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Konstantin Alexiou Manuel Wilbring Klaus Matschke Thomas Dschietzig Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.
description	<h4>Introduction</h4>Early allograft dysfunction following lung transplantation is mainly an ischemia/reperfusion (IR) injury. We showed that relaxin-2 (relaxin) exerts a protective effect in lung IR, attributable to decreases in endothelin-1 (ET-1) production, leukocyte recruitment, and free radical generation. Here, we summarize our investigations into relaxin's signalling.<h4>Materials and methods</h4>Isolated rat lungs were perfused with vehicle or 5 nM relaxin (n = 6-10 each). Thereafter, experiments were conducted in the presence of relaxin plus vehicle, the protein kinase A inhibitors H-89 and KT-5720, the NO synthase (NOS) inhibitor L-NAME, the iNOS inhibitor 1400W, the nNOS inhibitor SMTC, the extracellular signal-regulated kinase-1/2 (ERK-1/2) inhibitor PD-98059, the phosphatidylinositol-3 kinase (PI3K) inhibitor wortmannin, the endothelin type-B (ETB) antagonist A-192621, or the glucocorticoid receptor (GR) antagonist RU-486. After 90 min ischemia and 90 min reperfusion we determined wet-to-dry (W/D) weight ratio, mean pulmonary arterial pressure (MPAP), vascular release of ET-1, neutrophil elastase (NE), myeloperoxidase (MPO), and malondialdehyde (MDA). Primary rat pulmonary vascular cells were similarly treated.<h4>Results</h4>IR lungs displayed significantly elevated W/D ratios, MPAP, as well as ET-1, NE, MDA, and MPO. In the presence of relaxin, all of these parameters were markedly improved. This protective effect was completely abolished by L-NAME, 1400W, PD-98059, and wortmannin whereas neither PKA and nNOS inhibition nor ETB and GR antagonism were effective. Analysis of NOS gene expression and activity revealed that the relaxin-induced early and moderate iNOS stimulation is ERK-1/2-dependent and counter-balanced by PI3K. Relaxin-PI3K-related phosphorylation of a forkhead transcription factor, FKHRL1, paralleled this regulation. In pulmonary endothelial and smooth muscle cells, FKHRL1 was essential to relaxin-PI3K signalling towards iNOS.<h4>Conclusion</h4>In this short-time experimental setting, relaxin protects against IR-induced lung injury via early and moderate iNOS induction, dependent on balanced ERK-1/2 and PI3K-FKHRL1 stimulation. These findings render relaxin a candidate drug for lung preservation.
format	article
author	Konstantin Alexiou Manuel Wilbring Klaus Matschke Thomas Dschietzig
author_facet	Konstantin Alexiou Manuel Wilbring Klaus Matschke Thomas Dschietzig
author_sort	Konstantin Alexiou
title	Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.
title_short	Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.
title_full	Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.
title_fullStr	Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.
title_full_unstemmed	Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.
title_sort	relaxin protects rat lungs from ischemia-reperfusion injury via inducible no synthase: role of erk-1/2, pi3k, and forkhead transcription factor fkhrl1.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/4d1b84e7727d43b7a9d9c8ee62b8bf40
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Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.

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