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The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning
BACKGROUND: Pharmacologic studies with cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by COX-2. However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only rela...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402528/ https://www.ncbi.nlm.nih.gov/pubmed/22844439 http://dx.doi.org/10.1371/journal.pone.0041178 |
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author | Guo, Yiru Tukaye, Deepali Nivas Wu, Wen-Jian Zhu, Xiaoping Book, Michael Tan, Wei Jones, Steven P. Rokosh, Gregg Narumiya, Shuh Li, Qianhong Bolli, Roberto |
author_facet | Guo, Yiru Tukaye, Deepali Nivas Wu, Wen-Jian Zhu, Xiaoping Book, Michael Tan, Wei Jones, Steven P. Rokosh, Gregg Narumiya, Shuh Li, Qianhong Bolli, Roberto |
author_sort | Guo, Yiru |
collection | PubMed |
description | BACKGROUND: Pharmacologic studies with cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by COX-2. However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only relative. Furthermore, the specific prostaglandin (PG) receptors responsible for the salubrious actions of COX-2-derived prostanoids remain unclear. OBJECTIVE: To determine the role of COX-2 and prostacyclin receptor (IP) in late PC by gene deletion. METHODS: COX-2 knockout (KO) mice (COX-2(−/−)), prostacyclin receptor KO (IP(−/−)) mice, and respective wildtype (WT, COX-2(+/+) and IP(+/+)) mice underwent sham surgery or PC with six 4-min coronary occlusion (O)/4-min R cycles 24 h before a 30-min O/24 h R. RESULTS: There were no significant differences in infarct size (IS) between non-preconditioned (non-PC) COX-2(+/+), COX-2(−/−), IP(+/+), and IP(−/−) mice, indicating that neither COX-2 nor IP modulates IS in the absence of PC. When COX-2(−/−) or IP(−/−) mice were preconditioned, IS was not reduced, indicating that the protection of late PC was completely abrogated by deletion of either the COX-2 or the IP gene. Administration of the IP selective antagonist, RO3244794 to C57BL6/J (B6) mice 30 min prior to the 30-min O had no effect on IS. When B6 mice were preconditioned 24 h prior to the 30-min O, IS was markedly reduced; however, the protection of late PC was completely abrogated by pretreatment of RO3244794. CONCLUSIONS: This is the first study to demonstrate that targeted disruption of the COX-2 gene completely abrogates the infarct-sparing effect of late PC, and that the IP, downstream of the COX-2/prostanoid pathway, is a key mediator of the late PC. These results provide unequivocal molecular genetic evidence for an essential role of the COX-2/PGI2 receptor axis in the cardioprotection afforded by the late PC. |
format | Online Article Text |
id | pubmed-3402528 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34025282012-07-27 The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning Guo, Yiru Tukaye, Deepali Nivas Wu, Wen-Jian Zhu, Xiaoping Book, Michael Tan, Wei Jones, Steven P. Rokosh, Gregg Narumiya, Shuh Li, Qianhong Bolli, Roberto PLoS One Research Article BACKGROUND: Pharmacologic studies with cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by COX-2. However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only relative. Furthermore, the specific prostaglandin (PG) receptors responsible for the salubrious actions of COX-2-derived prostanoids remain unclear. OBJECTIVE: To determine the role of COX-2 and prostacyclin receptor (IP) in late PC by gene deletion. METHODS: COX-2 knockout (KO) mice (COX-2(−/−)), prostacyclin receptor KO (IP(−/−)) mice, and respective wildtype (WT, COX-2(+/+) and IP(+/+)) mice underwent sham surgery or PC with six 4-min coronary occlusion (O)/4-min R cycles 24 h before a 30-min O/24 h R. RESULTS: There were no significant differences in infarct size (IS) between non-preconditioned (non-PC) COX-2(+/+), COX-2(−/−), IP(+/+), and IP(−/−) mice, indicating that neither COX-2 nor IP modulates IS in the absence of PC. When COX-2(−/−) or IP(−/−) mice were preconditioned, IS was not reduced, indicating that the protection of late PC was completely abrogated by deletion of either the COX-2 or the IP gene. Administration of the IP selective antagonist, RO3244794 to C57BL6/J (B6) mice 30 min prior to the 30-min O had no effect on IS. When B6 mice were preconditioned 24 h prior to the 30-min O, IS was markedly reduced; however, the protection of late PC was completely abrogated by pretreatment of RO3244794. CONCLUSIONS: This is the first study to demonstrate that targeted disruption of the COX-2 gene completely abrogates the infarct-sparing effect of late PC, and that the IP, downstream of the COX-2/prostanoid pathway, is a key mediator of the late PC. These results provide unequivocal molecular genetic evidence for an essential role of the COX-2/PGI2 receptor axis in the cardioprotection afforded by the late PC. Public Library of Science 2012-07-23 /pmc/articles/PMC3402528/ /pubmed/22844439 http://dx.doi.org/10.1371/journal.pone.0041178 Text en Guo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Guo, Yiru Tukaye, Deepali Nivas Wu, Wen-Jian Zhu, Xiaoping Book, Michael Tan, Wei Jones, Steven P. Rokosh, Gregg Narumiya, Shuh Li, Qianhong Bolli, Roberto The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning |
title | The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning |
title_full | The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning |
title_fullStr | The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning |
title_full_unstemmed | The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning |
title_short | The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning |
title_sort | cox-2/pgi2 receptor axis plays an obligatory role in mediating the cardioprotection conferred by the late phase of ischemic preconditioning |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402528/ https://www.ncbi.nlm.nih.gov/pubmed/22844439 http://dx.doi.org/10.1371/journal.pone.0041178 |
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