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 (AT(1)) 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.

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Abstract-Release of norepinephrine (NE) by the hypothalamic nuclei may contribute to regulation of sympathetic nervous system (SNS) activity. Angiotensin-(1-7) [Ang-(1-7)] has an antihypertensive effect and may decrease SNS activity. We tested the hypothesis that Ang-(1-7) inhibits the release of NE in hypothalami, via the Ang-(1-7) and angiotensin II type 2 (AT 2 ) receptors, acting through a bradykinin (BK)/NO-dependent mechanism. Hypothalami from normotensive controls and spontaneously hypertensive rats (SHR) were isolated and endogenous NE stores labeled by incubating the tissues with [ 3 H]NE. [ 3 H]NE release from the hypothalami was stimulated by KCl in the presence or absence of Ang-(1-7) alone or combined with various antagonists and inhibitors. Ang-(1-7) significantly attenuated K ϩ -induced NE release by hypothalami from normotensive rats but was more potent in SHR. The Ang-(1-7) receptor antagonist ]Ang-(1-7), the AT 2 receptor antagonist PD 123319, and the BK B 2 receptor antagonist icatibant all blocked the inhibitory effect of Ang-(1-7) on K ϩ -stimulated NE release in SHR. The inhibitory effect of Ang-(1-7) disappeared in the presence of the NO synthase inhibitor N G -nitro-L-arginine methyl ester and was restored by the precursor of NO, L-arginine. The diminished NE release caused by Ang-(1-7) was blocked by a soluble guanylyl cyclase inhibitor as well as by a cGMP-dependent protein kinase (PKG). We concluded that Ang-(1-7) decreases NE release from the hypothalamus via the Ang-(1-7) or AT 2 receptors, acting through a BK/NO-mediated mechanism that stimulates cGMP/PKG signaling. In this way, Ang-(1-7) may decrease SNS activity and exert an antihypertensive effect. ] has been shown to be the most pleiotropic bioactive component of the renin-angiotensin system because it exerts effects that may be identical to, different from, or opposite from those displayed by angiotensin II (Ang II). 1 For instance, it lacks the vasoconstrictor aldosterone secretagogue or dipsogenic effects of Ang II. 1,2 However, it mimics Ang II stimulation of vasopressin and prostaglandin release 1 as well as peripheral norepinephrine (NE) outflow. 3 In contrast, Ang-(1-7) causes natriuresis, diuresis, and vasodilatation and inhibits angiogenesis and cellular growth, 1,2 suggesting that in many cases, this peptide may act as an endogenous antagonist of Ang II. In fact, Ang-(1-7) has been suggested as having an antihypertensive effect as well as counterbalancing the pressor and proliferative actions of Ang II because some of its effects that oppose those of Ang II are enhanced in rat models of hypertension. 1,4 It has been demonstrated that the Mas proto-oncogene, originally considered to be an "orphan" G-protein-coupled receptor involved in phospholipase C activation, 5 binds Ang-(1-7) and is involved in the biological actions of this heptapeptide. 6 Genetic deletion of the Mas receptor abolishes not only binding of Ang-(1-7) to mouse kidneys but also Ang-(1-7)-induced relaxation and antidiuretic responses, suggesting that ...