Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION
Autor(a) principal: | |
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Data de Publicação: | 2009 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/31679 https://dx.doi.org/10.1074/jbc.M109.021089 |
Resumo: | Bj-BPP-10c is a bioactive proline-rich decapeptide, part of the C-type natriuretic peptide precursor, expressed in the brain and in the venom gland of Bothrops jararaca. We recently showed that Bj-BPP-10c displays a strong, sustained anti-hypertensive effect in spontaneous hypertensive rats (SHR), without causing any effect in normotensive rats, by a pharmacological effect independent of angiotensin-converting enzyme inhibition. Therefore, we hypothesized that another mechanism should be involved in the peptide activity. Here we used affinity chromatography to search for kidney cytosolic proteins with affinity for Bj-BPP-10c and demonstrate that argininosuccinate synthetase (AsS) is the major protein binding to the peptide. More importantly, this interaction activates the catalytic activity of AsS in a dose-dependent manner. AsS is recognized as an important player of the citrulline-NO cycle that represents a potential limiting step in NO synthesis. Accordingly, the functional interaction of Bj-BPP-10c and AsS was evidenced by the following effects promoted by the peptide: (i) increase of NO metabolite production in human umbilical vein endothelial cell culture and of arginine in human embryonic kidney cells and (ii) increase of arginine plasma concentration in SHR. Moreover, alpha-methyl-DL-aspartic acid, a specific AsS inhibitor, significantly reduced the anti-hypertensive activity of Bj-BPP-10c in SHR. Taken together, these results suggest that AsS plays a role in the anti-hypertensive action of Bj-BPP-10c. Therefore, we propose the activation of AsS as a new mechanism for the anti-hypertensive effect of Bj-BPP-10c in SHR and AsS as a novel target for the therapy of hypertension-related diseases. |
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Guerreiro, Juliano R.Lameu, ClaudianaOliveira, Eduardo F. [UNIFESP]Klitzke, Clecio F.Melo, Robson L.Linares, EdlaineAugusto, OharaFox, Jay W.Lebrun, IvoSerrano, Solange M. T.Camargo, Antonio Carlos Martins de [UNIFESP]Inst ButantanUniversidade de São Paulo (USP)Universidade Federal de São Paulo (UNIFESP)Univ Virginia2016-01-24T13:58:32Z2016-01-24T13:58:32Z2009-07-24Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 284, n. 30, p. 20022-20033, 2009.0021-9258http://repositorio.unifesp.br/handle/11600/31679https://dx.doi.org/10.1074/jbc.M109.02108910.1074/jbc.M109.021089WOS:000268097400029Bj-BPP-10c is a bioactive proline-rich decapeptide, part of the C-type natriuretic peptide precursor, expressed in the brain and in the venom gland of Bothrops jararaca. We recently showed that Bj-BPP-10c displays a strong, sustained anti-hypertensive effect in spontaneous hypertensive rats (SHR), without causing any effect in normotensive rats, by a pharmacological effect independent of angiotensin-converting enzyme inhibition. Therefore, we hypothesized that another mechanism should be involved in the peptide activity. Here we used affinity chromatography to search for kidney cytosolic proteins with affinity for Bj-BPP-10c and demonstrate that argininosuccinate synthetase (AsS) is the major protein binding to the peptide. More importantly, this interaction activates the catalytic activity of AsS in a dose-dependent manner. AsS is recognized as an important player of the citrulline-NO cycle that represents a potential limiting step in NO synthesis. Accordingly, the functional interaction of Bj-BPP-10c and AsS was evidenced by the following effects promoted by the peptide: (i) increase of NO metabolite production in human umbilical vein endothelial cell culture and of arginine in human embryonic kidney cells and (ii) increase of arginine plasma concentration in SHR. Moreover, alpha-methyl-DL-aspartic acid, a specific AsS inhibitor, significantly reduced the anti-hypertensive activity of Bj-BPP-10c in SHR. Taken together, these results suggest that AsS plays a role in the anti-hypertensive action of Bj-BPP-10c. Therefore, we propose the activation of AsS as a new mechanism for the anti-hypertensive effect of Bj-BPP-10c in SHR and AsS as a novel target for the therapy of hypertension-related diseases.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Inst Butantan, Lab Especial Toxicol Aplicada, CAT CEPID, BR-05503900 São Paulo, BrazilUniv São Paulo, Inst Quim, Dept Bioquim, BR-05513970 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol Mol, BR-04044020 São Paulo, BrazilUniv Virginia, Dept Microbiol, Charlottesville, VA 22908 USAInst Butantan, Lab Bioquim & Biofis, BR-05503900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol Mol, BR-04044020 São Paulo, BrazilFAPESP: 98/14307-9FAPESP: 04/14250-0FAPESP: 06/53139-2FAPESP: 04/11359-0Web of Science20022-20033engAmer Soc Biochemistry Molecular Biology IncJournal of Biological ChemistryArgininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTIONinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP11600/316792023-01-24 22:20:16.953metadata only accessoai:repositorio.unifesp.br:11600/31679Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-01-25T01:20:16Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION |
title |
Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION |
spellingShingle |
Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION Guerreiro, Juliano R. |
title_short |
Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION |
title_full |
Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION |
title_fullStr |
Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION |
title_full_unstemmed |
Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION |
title_sort |
Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION |
author |
Guerreiro, Juliano R. |
author_facet |
Guerreiro, Juliano R. Lameu, Claudiana Oliveira, Eduardo F. [UNIFESP] Klitzke, Clecio F. Melo, Robson L. Linares, Edlaine Augusto, Ohara Fox, Jay W. Lebrun, Ivo Serrano, Solange M. T. Camargo, Antonio Carlos Martins de [UNIFESP] |
author_role |
author |
author2 |
Lameu, Claudiana Oliveira, Eduardo F. [UNIFESP] Klitzke, Clecio F. Melo, Robson L. Linares, Edlaine Augusto, Ohara Fox, Jay W. Lebrun, Ivo Serrano, Solange M. T. Camargo, Antonio Carlos Martins de [UNIFESP] |
author2_role |
author author author author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Inst Butantan Universidade de São Paulo (USP) Universidade Federal de São Paulo (UNIFESP) Univ Virginia |
dc.contributor.author.fl_str_mv |
Guerreiro, Juliano R. Lameu, Claudiana Oliveira, Eduardo F. [UNIFESP] Klitzke, Clecio F. Melo, Robson L. Linares, Edlaine Augusto, Ohara Fox, Jay W. Lebrun, Ivo Serrano, Solange M. T. Camargo, Antonio Carlos Martins de [UNIFESP] |
description |
Bj-BPP-10c is a bioactive proline-rich decapeptide, part of the C-type natriuretic peptide precursor, expressed in the brain and in the venom gland of Bothrops jararaca. We recently showed that Bj-BPP-10c displays a strong, sustained anti-hypertensive effect in spontaneous hypertensive rats (SHR), without causing any effect in normotensive rats, by a pharmacological effect independent of angiotensin-converting enzyme inhibition. Therefore, we hypothesized that another mechanism should be involved in the peptide activity. Here we used affinity chromatography to search for kidney cytosolic proteins with affinity for Bj-BPP-10c and demonstrate that argininosuccinate synthetase (AsS) is the major protein binding to the peptide. More importantly, this interaction activates the catalytic activity of AsS in a dose-dependent manner. AsS is recognized as an important player of the citrulline-NO cycle that represents a potential limiting step in NO synthesis. Accordingly, the functional interaction of Bj-BPP-10c and AsS was evidenced by the following effects promoted by the peptide: (i) increase of NO metabolite production in human umbilical vein endothelial cell culture and of arginine in human embryonic kidney cells and (ii) increase of arginine plasma concentration in SHR. Moreover, alpha-methyl-DL-aspartic acid, a specific AsS inhibitor, significantly reduced the anti-hypertensive activity of Bj-BPP-10c in SHR. Taken together, these results suggest that AsS plays a role in the anti-hypertensive action of Bj-BPP-10c. Therefore, we propose the activation of AsS as a new mechanism for the anti-hypertensive effect of Bj-BPP-10c in SHR and AsS as a novel target for the therapy of hypertension-related diseases. |
publishDate |
2009 |
dc.date.issued.fl_str_mv |
2009-07-24 |
dc.date.accessioned.fl_str_mv |
2016-01-24T13:58:32Z |
dc.date.available.fl_str_mv |
2016-01-24T13:58:32Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 284, n. 30, p. 20022-20033, 2009. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/31679 https://dx.doi.org/10.1074/jbc.M109.021089 |
dc.identifier.issn.none.fl_str_mv |
0021-9258 |
dc.identifier.doi.none.fl_str_mv |
10.1074/jbc.M109.021089 |
dc.identifier.wos.none.fl_str_mv |
WOS:000268097400029 |
identifier_str_mv |
Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 284, n. 30, p. 20022-20033, 2009. 0021-9258 10.1074/jbc.M109.021089 WOS:000268097400029 |
url |
http://repositorio.unifesp.br/handle/11600/31679 https://dx.doi.org/10.1074/jbc.M109.021089 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.none.fl_str_mv |
Journal of Biological Chemistry |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
20022-20033 |
dc.publisher.none.fl_str_mv |
Amer Soc Biochemistry Molecular Biology Inc |
publisher.none.fl_str_mv |
Amer Soc Biochemistry Molecular Biology Inc |
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 |
|
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1802764274851905536 |