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Angiotensin-(1–7) stimulates the phosphorylation of JAK2, IRS-1 and Akt in rat heart in vivo: role of the AT₁ and Mas receptors

Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Tecnológicas, Buenos Aires, Argentina

Submitted 20 December 2006 ; accepted in final form 5 May 2007

Angiotensin (ANG) II exerts a negative modulation on insulin signal transduction that might be involved in the pathogenesis of hypertension and insulin resistance. ANG-(1–7), an endogenous heptapeptide hormone formed by cleavage of ANG I and ANG II, counteracts many actions of ANG II. In the current study, we have explored the role of ANG-(1–7) in the signaling crosstalk that exists between ANG II and insulin. We demonstrated that ANG-(1–7) stimulates the phosphorylation of Janus kinase 2 (JAK2) and insulin receptor substrate (IRS)-1 in rat heart in vivo. This stimulating effect was blocked by administration of the selective ANG type 1 (AT₁) receptor blocker losartan. In contrast to ANG II, ANG-(1–7) stimulated cardiac Akt phosphorylation, and this stimulation was blunted in presence of the receptor Mas antagonist A-779 or the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. The specific JAK2 inhibitor AG-490 blocked ANG-(1–7)-induced JAK2 and IRS-1 phosphorylation but had no effect on ANG-(1–7)-induced phosphorylation of Akt, indicating that activation of cardiac Akt by ANG-(1–7) appears not to involve the recruitment of JAK2 but proceeds through the receptor Mas and involves PI3K. Acute in vivo insulin-induced cardiac Akt phosphorylation was inhibited by ANG II. Interestingly, coadministration of insulin with an equimolar mixture of ANG II and ANG-(1–7) reverted this inhibitory effect. On the basis of our present results, we postulate that ANG-(1–7) could be a positive physiological contributor to the actions of insulin in heart and that the balance between ANG II and ANG-(1–7) could be relevant for the association among insulin resistance, hypertension, and cardiovascular disease.

angiotensin II; Janus kinase; insulin receptor substrate-1; signal transduction

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