Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors
Autor(a) principal: | |
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Data de Publicação: | 2010 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
dARK ID: | ark:/48912/0013000012758 |
Texto Completo: | http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.156877 http://repositorio.unifesp.br/handle/11600/32927 |
Resumo: | Previous reports have shown that heparin may promote human hypotension and vascular relaxation by elevation of NO levels through unclear mechanisms. We hypothesized that endothelial muscarinic M-3 receptor activation mediates the heparin-induced vasodilation of rat aortic rings. the experiments were carried out using unfractionated heparin extracted from bovine intestinal mucosa, which elicited an endothelium and NO-dependent relaxation of aortic segments with maximal potency and efficacy (EC50: 100 +/- 10 mu mol/L; E-max: 41 +/- 3%). Atropine and 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide inhibitors reduced the heparin-dependent relaxation, indicating that M-3 muscarinic receptor is involved in this phenomenon. However, no direct binding of heparin to muscarinic receptors was observed. More importantly, studies performed using the arginine-glycine-aspartic acid peptide and 1-(1,1-dimethylethyl)-3-(1-naphthalenyl)-1H-pyrazolo[3,4-day]pyrimidin-4-amine, an Src family inhibitor, reduced by 51% and 73% the heparin-dependent relaxation, respectively, suggesting the coupling of heparin and M-3 receptor through extracellular matrix molecules and integrin. Furthermore, unfractionated heparin induced activation of focal adhesion protein kinase, Src, and paxillin. Finally, fluorescence resonance energy transfer approach confirmed the interaction of the M-3 receptor to integrin. Taken together, these data demonstrate the participation of M-3 receptor and integrin in heparin-dependent relaxation of vascular smooth muscle. These results provide new insights into the molecular mechanism and potential pharmacological action of heparin in vascular physiology. (Hypertension. 2010;56:713-721.) |
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Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptorsheparinmuscarinic receptorsM-3 receptorintegrinsmooth muscle relaxationaortaPrevious reports have shown that heparin may promote human hypotension and vascular relaxation by elevation of NO levels through unclear mechanisms. We hypothesized that endothelial muscarinic M-3 receptor activation mediates the heparin-induced vasodilation of rat aortic rings. the experiments were carried out using unfractionated heparin extracted from bovine intestinal mucosa, which elicited an endothelium and NO-dependent relaxation of aortic segments with maximal potency and efficacy (EC50: 100 +/- 10 mu mol/L; E-max: 41 +/- 3%). Atropine and 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide inhibitors reduced the heparin-dependent relaxation, indicating that M-3 muscarinic receptor is involved in this phenomenon. However, no direct binding of heparin to muscarinic receptors was observed. More importantly, studies performed using the arginine-glycine-aspartic acid peptide and 1-(1,1-dimethylethyl)-3-(1-naphthalenyl)-1H-pyrazolo[3,4-day]pyrimidin-4-amine, an Src family inhibitor, reduced by 51% and 73% the heparin-dependent relaxation, respectively, suggesting the coupling of heparin and M-3 receptor through extracellular matrix molecules and integrin. Furthermore, unfractionated heparin induced activation of focal adhesion protein kinase, Src, and paxillin. Finally, fluorescence resonance energy transfer approach confirmed the interaction of the M-3 receptor to integrin. Taken together, these data demonstrate the participation of M-3 receptor and integrin in heparin-dependent relaxation of vascular smooth muscle. These results provide new insights into the molecular mechanism and potential pharmacological action of heparin in vascular physiology. (Hypertension. 2010;56:713-721.)Universidade Federal de São Paulo, Dept Biochem, BR-04044020 São Paulo, BrazilUniv Fed Parana, Dept Biol Celular, BR-80060000 Curitiba, Parana, BrazilUniversidade Federal de São Paulo, Dept Biochem, BR-04044020 São Paulo, BrazilWeb of ScienceFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Financiadora de Estudos e ProjetosCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FAPESP: 2006/61006-2Lippincott Williams & WilkinsUniversidade Federal de São Paulo (UNIFESP)Univ Fed ParanaParedes-Gamero, Edgar Julian [UNIFESP]Medeiros, Valquiria Pereira de [UNIFESP]Farias, Eduardo Henrique Cunha de [UNIFESP]Justo, Giselle Zenker [UNIFESP]Trindade, Edvaldo da Silva [UNIFESP]Andrade-Lopes, Ana L.Godinho, Rosely Oliveira [UNIFESP]Miranda, Antonio [UNIFESP]Ferreira, Alice Teixeira [UNIFESP]Tersariol, Ivarne Luis dos Santos [UNIFESP]Nader, Helena Bonciani [UNIFESP]2016-01-24T14:05:29Z2016-01-24T14:05:29Z2010-10-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion713-U282http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.156877Hypertension. Philadelphia: Lippincott Williams & Wilkins, v. 56, n. 4, p. 713-U282, 2010.10.1161/HYPERTENSIONAHA.110.1568770194-911Xhttp://repositorio.unifesp.br/handle/11600/32927WOS:000281881400026ark:/48912/0013000012758engHypertensioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP2016-01-24T12:05:29Zoai:repositorio.unifesp.br/:11600/32927Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestbiblioteca.csp@unifesp.bropendoar:34652024-12-11T20:51:09.168423Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.none.fl_str_mv |
Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors |
title |
Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors |
spellingShingle |
Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors Paredes-Gamero, Edgar Julian [UNIFESP] heparin muscarinic receptors M-3 receptor integrin smooth muscle relaxation aorta |
title_short |
Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors |
title_full |
Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors |
title_fullStr |
Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors |
title_full_unstemmed |
Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors |
title_sort |
Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors |
author |
Paredes-Gamero, Edgar Julian [UNIFESP] |
author_facet |
Paredes-Gamero, Edgar Julian [UNIFESP] Medeiros, Valquiria Pereira de [UNIFESP] Farias, Eduardo Henrique Cunha de [UNIFESP] Justo, Giselle Zenker [UNIFESP] Trindade, Edvaldo da Silva [UNIFESP] Andrade-Lopes, Ana L. Godinho, Rosely Oliveira [UNIFESP] Miranda, Antonio [UNIFESP] Ferreira, Alice Teixeira [UNIFESP] Tersariol, Ivarne Luis dos Santos [UNIFESP] Nader, Helena Bonciani [UNIFESP] |
author_role |
author |
author2 |
Medeiros, Valquiria Pereira de [UNIFESP] Farias, Eduardo Henrique Cunha de [UNIFESP] Justo, Giselle Zenker [UNIFESP] Trindade, Edvaldo da Silva [UNIFESP] Andrade-Lopes, Ana L. Godinho, Rosely Oliveira [UNIFESP] Miranda, Antonio [UNIFESP] Ferreira, Alice Teixeira [UNIFESP] Tersariol, Ivarne Luis dos Santos [UNIFESP] Nader, Helena Bonciani [UNIFESP] |
author2_role |
author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Federal de São Paulo (UNIFESP) Univ Fed Parana |
dc.contributor.author.fl_str_mv |
Paredes-Gamero, Edgar Julian [UNIFESP] Medeiros, Valquiria Pereira de [UNIFESP] Farias, Eduardo Henrique Cunha de [UNIFESP] Justo, Giselle Zenker [UNIFESP] Trindade, Edvaldo da Silva [UNIFESP] Andrade-Lopes, Ana L. Godinho, Rosely Oliveira [UNIFESP] Miranda, Antonio [UNIFESP] Ferreira, Alice Teixeira [UNIFESP] Tersariol, Ivarne Luis dos Santos [UNIFESP] Nader, Helena Bonciani [UNIFESP] |
dc.subject.por.fl_str_mv |
heparin muscarinic receptors M-3 receptor integrin smooth muscle relaxation aorta |
topic |
heparin muscarinic receptors M-3 receptor integrin smooth muscle relaxation aorta |
description |
Previous reports have shown that heparin may promote human hypotension and vascular relaxation by elevation of NO levels through unclear mechanisms. We hypothesized that endothelial muscarinic M-3 receptor activation mediates the heparin-induced vasodilation of rat aortic rings. the experiments were carried out using unfractionated heparin extracted from bovine intestinal mucosa, which elicited an endothelium and NO-dependent relaxation of aortic segments with maximal potency and efficacy (EC50: 100 +/- 10 mu mol/L; E-max: 41 +/- 3%). Atropine and 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide inhibitors reduced the heparin-dependent relaxation, indicating that M-3 muscarinic receptor is involved in this phenomenon. However, no direct binding of heparin to muscarinic receptors was observed. More importantly, studies performed using the arginine-glycine-aspartic acid peptide and 1-(1,1-dimethylethyl)-3-(1-naphthalenyl)-1H-pyrazolo[3,4-day]pyrimidin-4-amine, an Src family inhibitor, reduced by 51% and 73% the heparin-dependent relaxation, respectively, suggesting the coupling of heparin and M-3 receptor through extracellular matrix molecules and integrin. Furthermore, unfractionated heparin induced activation of focal adhesion protein kinase, Src, and paxillin. Finally, fluorescence resonance energy transfer approach confirmed the interaction of the M-3 receptor to integrin. Taken together, these data demonstrate the participation of M-3 receptor and integrin in heparin-dependent relaxation of vascular smooth muscle. These results provide new insights into the molecular mechanism and potential pharmacological action of heparin in vascular physiology. (Hypertension. 2010;56:713-721.) |
publishDate |
2010 |
dc.date.none.fl_str_mv |
2010-10-01 2016-01-24T14:05:29Z 2016-01-24T14:05:29Z |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.156877 Hypertension. Philadelphia: Lippincott Williams & Wilkins, v. 56, n. 4, p. 713-U282, 2010. 10.1161/HYPERTENSIONAHA.110.156877 0194-911X http://repositorio.unifesp.br/handle/11600/32927 WOS:000281881400026 |
dc.identifier.dark.fl_str_mv |
ark:/48912/0013000012758 |
url |
http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.156877 http://repositorio.unifesp.br/handle/11600/32927 |
identifier_str_mv |
Hypertension. Philadelphia: Lippincott Williams & Wilkins, v. 56, n. 4, p. 713-U282, 2010. 10.1161/HYPERTENSIONAHA.110.156877 0194-911X WOS:000281881400026 ark:/48912/0013000012758 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Hypertension |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
713-U282 |
dc.publisher.none.fl_str_mv |
Lippincott Williams & Wilkins |
publisher.none.fl_str_mv |
Lippincott Williams & Wilkins |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UNIFESP instname:Universidade Federal de São Paulo (UNIFESP) instacron:UNIFESP |
instname_str |
Universidade Federal de São Paulo (UNIFESP) |
instacron_str |
UNIFESP |
institution |
UNIFESP |
reponame_str |
Repositório Institucional da UNIFESP |
collection |
Repositório Institucional da UNIFESP |
repository.name.fl_str_mv |
Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP) |
repository.mail.fl_str_mv |
biblioteca.csp@unifesp.br |
_version_ |
1818602554879115264 |