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1 Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), UBA-CONICET, Facultad de Farmacia y Bioquímica, Capital Federal, Argentina
2 Capital Federal, Argentina; Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), UBA-CONICET, Facultad de Farmacia y Bioquímica, Capital Federal, Argentina
3 Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), UBA-CONICET, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina
* To whom correspondence should be addressed. E-mail: dominici{at}qb.ffyb.uba.ar.
Angiotensin (ANG) II exerts a negative modulation on insulin signal transduction that might be involved in the pathogenesis of hypertension and insulin resistance. Angiotensin-(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 (JAK) 2 and IRS-1 in rat heart in vivo. This stimulating effect was blocked by the 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 PI 3-kinase 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 PI 3-kinase. Acute in vivo insulin-induced cardiac Akt phosphorylation was inhibited by ANG II. Interestingly, co-administration of insulin with an equimolar mixture of ANG II and ANG-(1-7) reverted this inhibitory effect. Based on 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 between insulin resistance, hypertension and cardiovascular disease.
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