Heparin Induces Rat Aorta Relaxation via Integrin-Dependent Activation of Muscarinic M-3 Receptors

Detalhes bibliográficos
Autor(a) principal: Paredes-Gamero, Edgar Julian [UNIFESP]
Data de Publicação: 2010
Outros Autores: 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]
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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spelling 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
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