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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

¹ Department of Internal Medicine, State University of Campinas, UNICAMP, Campinas, Brazil
² Department of Pharmacology, State University of Campinas, UNICAMP, Campinas, Brazil

Address correspondence and reprint requests to Mario J.A. Saad, Department of Internal Medicine, State University of Campinas, UNICAMP, Campinas 13083-970, Brazil. E-mail: msaad{at}fcm.unicamp.br

Abbreviations: ACh, acetylcholine; eNOS, endothelial cell–nitric oxide synthase; ERK, extracellular signal–regulated kinase; GTN, gryceryl trinitrate; IR, insulin receptor; IRS, insulin receptor substrate; JAK2, Janus kinase 2; MAPK, mitogen-activated protein kinase; PI, phosphatidylinositol

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.

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