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Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats.
Zecchin, Henrique G; Priviero, Fernanda B M; Souza, Claudio T; Zecchin, Karina G; Prada, Patrícia O; Carvalheira, José B C; Velloso, Licio A; Antunes, Edson; Saad, Mario J A.
Afiliação
  • Zecchin HG; Department of Internal Medicine, State University of Campinas, UNICAMP, Campinas 13083-970, Brazil.
Diabetes ; 56(4): 1014-24, 2007 Apr.
Article em En | MEDLINE | ID: mdl-17229938
The actions of acetylcholine (ACh) on endothelium mainly are mediated through muscarinic receptors, which are members of the G protein-coupled receptor family. In the present study, we show that ACh induces rapid tyrosine phosphorylation and activation of Janus kinase 2 (JAK2) in rat aorta. Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase (eNOS), and extracellular signal-regulated kinase (ERK)-1/2. The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyperactivated ERK/mitogen-activated protein kinase pathway. These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor de Insulina / Endotélio Vascular / Acetilcolina / Óxido Nítrico Sintase Tipo III / Proteínas Proto-Oncogênicas c-akt / Insulina / Obesidade Limite: Animals Idioma: En Revista: Diabetes Ano de publicação: 2007 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor de Insulina / Endotélio Vascular / Acetilcolina / Óxido Nítrico Sintase Tipo III / Proteínas Proto-Oncogênicas c-akt / Insulina / Obesidade Limite: Animals Idioma: En Revista: Diabetes Ano de publicação: 2007 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos