Angiotensin-(1-7) stimulates the phosphorylation of JAK2, IRS-1 and AKT in rat heart in vivo. Role of the AT1 and Mas receptors

GIANI JF; GIRONACCI MM; MUÑOZ MC; TURYN D; DOMINICI FP

Miami, EEUU

Congreso; XVIIth Session of the Interamerican Society of Hipertension.; 2007

IASH

The heart is one of the main targets for ANG-(1-7) action and since it is also an insulin-responsive organ, disorders of insulin action, such as diabetes and obesity, can have profound effects on cardiac performance. OBJECTIVE Our aim was to study the effect of ANG-(1-7) in Janus kinase (JAK) 2, IRS-1 and Akt phosphorylation in the rat heart and to determine the receptors involved. In addition, we analyzed the role of ANG-(1-7) in the interaction between the insulin signaling cascade and the ANG II. METHODS Male Sprague-Dawley rats at 8 weeks of age were used. Insulin, ANG II and ANG-(1-7) were administrated at 10 nM into the cava vein and after 5 minutes hearts were removed and homogenized. Protein abundance and phosphorylation of JAK2, IRS-1 and Akt were determined by immunoblotting. RESULTS ANG-(1-7) stimulated JAK2 and IRS-1 tyrosine phosphorylation in vivo (3-fold increase), this stimulation was blocked by losartan showing that ANG type 1 (AT1) receptors are involved. In contrast to ANG II, ANG-(1-7) stimulated cardiac Akt phosphorylation (3 fold increase), which was blunted in the presence of the receptor Mas antagonist A-779. Moreover, 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, suggesting that activation of cardiac Akt by ANG-(1-7) does not involve the recruitment of JAK2. In agreement with previous results, we showed that ANG II attenuated the insulin-stimulated phosphorylation of Akt at Ser473 in the rat heart. Interestingly, when ANG-(1-7) was administered simultaneously with ANG II and insulin, a clear restitution of the insulin-stimulated phosphorylation of Akt was observed, showing that ANG-(1-7) ameliorates the detrimental effects exerted by ANG II at this level.  CONCLUSIONS Based on our results, we postulate that ANG-(1-7) could be a positive physiological contributor to the insulin actions in the heart and that the balance between ANG II and ANG-(1-7) is important for the association between insulin resistance, hypertension and cardiovascular disease.