Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION

Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide ROLE in ARGININE and NITRIC OXIDE PRODUCTION

Author Guerreiro, Juliano R. Google Scholar
Lameu, Claudiana Google Scholar
Oliveira, Eduardo F. Autor UNIFESP Google Scholar
Klitzke, Clecio F. Google Scholar
Melo, Robson L. Google Scholar
Linares, Edlaine Google Scholar
Augusto, Ohara Google Scholar
Fox, Jay W. Google Scholar
Lebrun, Ivo Google Scholar
Serrano, Solange M. T. Google Scholar
Camargo, Antonio Carlos Martins de Autor UNIFESP Google Scholar
Institution Inst Butantan
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Univ Virginia
Abstract 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.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 98/14307-9
FAPESP: 04/14250-0
FAPESP: 06/53139-2
FAPESP: 04/11359-0
Date 2009-07-24
Published in Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 284, n. 30, p. 20022-20033, 2009.
ISSN 0021-9258 (Sherpa/Romeo, impact factor)
Publisher Amer Soc Biochemistry Molecular Biology Inc
Extent 20022-20033
Origin http://dx.doi.org/10.1074/jbc.M109.021089
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000268097400029
URI http://repositorio.unifesp.br/handle/11600/31679

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