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Type: Artigo de periódico
Title: Defective Insulin And Acetylcholine Induction Of Endothelial Cell-nitric Oxide Synthase Through Insulin Receptor Substrate/akt Signaling Pathway In Aorta Of Obese Rats.
Author: 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
Abstract: 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.
Subject: Acetylcholine
Dietary Fats
Endothelium, Vascular
Energy Intake
Enzyme Induction
Janus Kinase 2
Nitric Oxide Synthase Type Iii
Proto-oncogene Proteins C-akt
Rats, Mutant Strains
Rats, Wistar
Receptor, Insulin
Signal Transduction
Citation: Diabetes. v. 56, n. 4, p. 1014-24, 2007-Apr.
Rights: fechado
Identifier DOI: 10.2337/db05-1147
Date Issue: 2007
Appears in Collections:Unicamp - Artigos e Outros Documentos

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