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Cardiovascular Research 1998 40(1):96-102; doi:10.1016/S0008-6363(98)00098-4
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Insulin signalling in heart involves insulin receptor substrates-1 and -2, activation of phosphatidylinositol 3-kinase and the JAK 2-growth related pathway

Licio A. Vellosoa,*, Carla R.O. Carvalhoa, Fernanda A. Rojasa, Franco Follib and Mario J.A. Saada

aDepartment of Internal Medicine, University of Campinas—UNICAMP, 13081-970 Campinas SP, Brazil
bDepartment of Medicine I, H.S. Raffaele, Milan, Italy

* Corresponding author. Tel.: +55 (19) 239 7734; Fax: +55 (19) 239 3114.

Objective: Hyperinsulinemia is a common feature of obesity and hypertension and may be associated with abnormal metabolism and growth of heart muscle and vascular wall. Most of the known actions of insulin were characterised in muscle, adipose tissue and liver. In this study we investigate the initial steps of insulin signalling in rat heart. Methods: After insulin infusion in the cava vein of male Wistar rats, the insulin receptor, insulin receptor substrates-1 and -2, phosphatidylinositol 3-kinase activity and Janus kinase (JAK) 2 engagement were studied by immunoprecipitation and immunoblot of heart extracts. Results: An insulin load induces rapid autophosphorylation of the insulin receptor which is followed by the phosphorylation of insulin receptor substrates-1 and -2. The phosphorylation of these early intracellular substrates leads to the association of the p85 subunit of phosphatidylinositol 3-kinase and subsequent activation of its catalytic p110 subunit. Besides activation of the lipid metabolising enzyme phosphatidylinositol 3-kinase, the phosphorylation of insulin receptor substrates-1 and -2 engages the intracellular kinase JAK 2 and induces JAK 2–STAT 1 complex formation. Conclusion: We demonstrate that the early steps of insulin signalling in heart include the phosphorylation–activation of the insulin receptor, engagement of insulin receptor substrates-1 and -2 with the consequent activation of phosphatidylinositol 3-kinase and the involvement of the recently discovered growth related pathway—JAK 2–STAT 1.

KEYWORDS Insulin receptor; Insulin receptor substrate-1 and -2; Phosphatidylinositol 3-kinase; JAK 2; Heart hypertrophy; Rat


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