Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension
Oxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiot...
| Autores: | , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2009 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/18527 |
| Acceso en línea: | https://hdl.handle.net/10171/18527 |
| Access Level: | acceso abierto |
| Palabra clave: | EXP3179 Hypertension Losartan Metalloproteinases NADPH oxidase PKC |
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Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertensionFortuño, A. (Ana)|||/items/2324831f-71b3-4d1b-afc1-594e4e1bc0c9Bidegain, J. (J.)|||/items/19022081-f59e-4202-9ed2-b056a4e4b584Robador, P.A. (Pablo A.)|||/items/35b849ed-5afe-44ce-bd97-b7bf1ba0a307Hermida-Santos, J. (José)|||/items/9e67bdb3-d55d-4819-847e-9b44cc487fdbLopez-Sagaseta, J. (Jacinto)|||/items/ad7d0167-0d3c-4975-a77e-b64545be8010Beloqui, O. (Óscar)|||/items/87d04a14-2d74-4221-8a57-12550777420dDiez-Martinez, J. (Javier)|||/items/4f3a0e43-12bf-403d-9dc7-31fab0d11d41Zalba-Goñi, G. (Guillermo)|||/items/71410fa2-baa5-4efc-bce7-14b4b0e23802EXP3179HypertensionLosartanMetalloproteinasesNADPH oxidasePKCOxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiotensin II type 1 receptor antagonist losartan and its metabolites (EXP3174 and EXP3179) on NADPH oxidase activity and MMP-9 secretion in human phagocytic cells. EXP3179, but not losartan and EXP3174, dose-dependently inhibited (P<0.05) phorbol myristate acetate and insulin-stimulated NADPH oxidase activity. EXP3179 also inhibited phorbol myristate acetate-induced NADPH oxidase in endothelial cells. In addition, EXP3179 inhibited (P<0.05) both phorbol myristate acetate-stimulated p47phox translocation from cytosol to membranes and protein kinase C activity. Affinity experiments and enzymatic assays confirmed that EXP3179 inhibited several protein kinase C isoforms. EXP3179 also inhibited (P<0.05) phorbol myristate acetate-stimulated MMP-9 secretion. In a study performed in 153 hypertensive patients, phagocytic NADPH oxidase activity was lower (P<0.05) in losartan-treated compared with untreated patients and in patients treated with other angiotensin II type 1 receptor antagonists or with angiotensin-converting enzyme inhibitors. Plasma levels of MMP-9 were lower (P<0.05) in losartan-treated hypertensives compared with the other group of patients. Thus, EXP3179 acts as a blocker of the NADPH oxidase in phagocytic cells by a potential mechanism that targets the protein kinase C signaling pathway. This effect can be involved in reduced MMP-9 secretion by these cells. It is proposed that the EXP3179 metabolite may confer to losartan the specific capacity to reduce oxidative stress mediated by phagocytic cells in hypertensive patients.American Heart AssociationDadun. Depósito Académico Digital Universidad de Navarra20112011-06-1320092009-01-0120092009-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/18527reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/185272026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension |
| title |
Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension |
| spellingShingle |
Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension Fortuño, A. (Ana)|||/items/2324831f-71b3-4d1b-afc1-594e4e1bc0c9 EXP3179 Hypertension Losartan Metalloproteinases NADPH oxidase PKC |
| title_short |
Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension |
| title_full |
Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension |
| title_fullStr |
Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension |
| title_full_unstemmed |
Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension |
| title_sort |
Losartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertension |
| dc.creator.none.fl_str_mv |
Fortuño, A. (Ana)|||/items/2324831f-71b3-4d1b-afc1-594e4e1bc0c9 Bidegain, J. (J.)|||/items/19022081-f59e-4202-9ed2-b056a4e4b584 Robador, P.A. (Pablo A.)|||/items/35b849ed-5afe-44ce-bd97-b7bf1ba0a307 Hermida-Santos, J. (José)|||/items/9e67bdb3-d55d-4819-847e-9b44cc487fdb Lopez-Sagaseta, J. (Jacinto)|||/items/ad7d0167-0d3c-4975-a77e-b64545be8010 Beloqui, O. (Óscar)|||/items/87d04a14-2d74-4221-8a57-12550777420d Diez-Martinez, J. (Javier)|||/items/4f3a0e43-12bf-403d-9dc7-31fab0d11d41 Zalba-Goñi, G. (Guillermo)|||/items/71410fa2-baa5-4efc-bce7-14b4b0e23802 |
| author |
Fortuño, A. (Ana)|||/items/2324831f-71b3-4d1b-afc1-594e4e1bc0c9 |
| author_facet |
Fortuño, A. (Ana)|||/items/2324831f-71b3-4d1b-afc1-594e4e1bc0c9 Bidegain, J. (J.)|||/items/19022081-f59e-4202-9ed2-b056a4e4b584 Robador, P.A. (Pablo A.)|||/items/35b849ed-5afe-44ce-bd97-b7bf1ba0a307 Hermida-Santos, J. (José)|||/items/9e67bdb3-d55d-4819-847e-9b44cc487fdb Lopez-Sagaseta, J. (Jacinto)|||/items/ad7d0167-0d3c-4975-a77e-b64545be8010 Beloqui, O. (Óscar)|||/items/87d04a14-2d74-4221-8a57-12550777420d Diez-Martinez, J. (Javier)|||/items/4f3a0e43-12bf-403d-9dc7-31fab0d11d41 Zalba-Goñi, G. (Guillermo)|||/items/71410fa2-baa5-4efc-bce7-14b4b0e23802 |
| author_role |
author |
| author2 |
Bidegain, J. (J.)|||/items/19022081-f59e-4202-9ed2-b056a4e4b584 Robador, P.A. (Pablo A.)|||/items/35b849ed-5afe-44ce-bd97-b7bf1ba0a307 Hermida-Santos, J. (José)|||/items/9e67bdb3-d55d-4819-847e-9b44cc487fdb Lopez-Sagaseta, J. (Jacinto)|||/items/ad7d0167-0d3c-4975-a77e-b64545be8010 Beloqui, O. (Óscar)|||/items/87d04a14-2d74-4221-8a57-12550777420d Diez-Martinez, J. (Javier)|||/items/4f3a0e43-12bf-403d-9dc7-31fab0d11d41 Zalba-Goñi, G. (Guillermo)|||/items/71410fa2-baa5-4efc-bce7-14b4b0e23802 |
| author2_role |
author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
EXP3179 Hypertension Losartan Metalloproteinases NADPH oxidase PKC |
| topic |
EXP3179 Hypertension Losartan Metalloproteinases NADPH oxidase PKC |
| description |
Oxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiotensin II type 1 receptor antagonist losartan and its metabolites (EXP3174 and EXP3179) on NADPH oxidase activity and MMP-9 secretion in human phagocytic cells. EXP3179, but not losartan and EXP3174, dose-dependently inhibited (P<0.05) phorbol myristate acetate and insulin-stimulated NADPH oxidase activity. EXP3179 also inhibited phorbol myristate acetate-induced NADPH oxidase in endothelial cells. In addition, EXP3179 inhibited (P<0.05) both phorbol myristate acetate-stimulated p47phox translocation from cytosol to membranes and protein kinase C activity. Affinity experiments and enzymatic assays confirmed that EXP3179 inhibited several protein kinase C isoforms. EXP3179 also inhibited (P<0.05) phorbol myristate acetate-stimulated MMP-9 secretion. In a study performed in 153 hypertensive patients, phagocytic NADPH oxidase activity was lower (P<0.05) in losartan-treated compared with untreated patients and in patients treated with other angiotensin II type 1 receptor antagonists or with angiotensin-converting enzyme inhibitors. Plasma levels of MMP-9 were lower (P<0.05) in losartan-treated hypertensives compared with the other group of patients. Thus, EXP3179 acts as a blocker of the NADPH oxidase in phagocytic cells by a potential mechanism that targets the protein kinase C signaling pathway. This effect can be involved in reduced MMP-9 secretion by these cells. It is proposed that the EXP3179 metabolite may confer to losartan the specific capacity to reduce oxidative stress mediated by phagocytic cells in hypertensive patients. |
| publishDate |
2009 |
| dc.date.none.fl_str_mv |
2009 2009-01-01 2009 2009-01-01 2011 2011-06-13 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/18527 |
| url |
https://hdl.handle.net/10171/18527 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
American Heart Association |
| publisher.none.fl_str_mv |
American Heart Association |
| dc.source.none.fl_str_mv |
reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
| instname_str |
Universidad de Navarra |
| reponame_str |
Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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|
| repository.mail.fl_str_mv |
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1869416101545246720 |
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15.300719 |