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, PEÑA C, TURYN D, DOMINICI FP.

MIami

Congreso; XVII Session of the Interamerican Society of Hipertension; 2007

Inter-American Society of Hypertension

The renin angiotensin system (RAS) is a potent regulator of blood pressure and plays a major role in the pathogenesis of cardiovascular disease. Until recently, most studies conducted to reveal the mechanisms contributing to high blood pressure focused on the actions of angiotensin (ANG) II. This hormone initiates signals that increase blood pressure and also plays an important role in cardiovascular and neuroendocrine physiology and electrolytes homeostasis. The identification of novel biochemical components of the RAS has added a further layer of complexity to the classical concept of this cardiovascular regulatory system. It is now clear that there is a counter-regulatory arm within the RAS in which angiotensin (ANG)-(1-7) plays a major role. Angiotensin-(1–7) is an endogenous heptapeptide hormone formed by cleavage of ANG I by neutral endopeptidases and also from ANG II by the angiotensin-converting enzyme homologue (ACE2).Cross-talk between the RAS and the insulin signaling system has drawn great attention because hypertension and insulin resistance often coexist and are primary risk factors for cardiovascular disease. Recently, a series of studies revealed a connection between the signal transduction pathways that mediate insulin and ANG II actions in target tissues. Upon insulin binding, the insulin receptor (IR) becomes activated leading to the tyrosine phosphorylation of several intracellular proteins, including insulin receptor substrate (IRS)-1 and IRS-2. Many of the effects of insulin are mediated by activation of the enzyme phosphatidylinositol 3-kinase (PI3K) and downstream signaling pathways, including protein kinase B (Akt).In this study, we analyzed the role of ANG-(1-7) in the interaction between the insulin signaling cascade and the RAS in rat heart. 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.Angiotensin II and ANG-(1-7) were administrated into the cava vein, after 5 minutes hearts were removed and solubilized. Phosphorylation and protein abundance were determined by inmunoblotting.We demonstrated that ANG-(1-7) stimulates Janus kinase (JAK) 2 phosphorylation and induces the phosphorylation of IRS-1 and Akt in rat heart in vivo. Angiotensin-(1-7)-stimulated phosphorylation of JAK2 and IRS-1 was blocked by losartan showing that this effect is mediated by the ANG type 1 (AT1) receptor. 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. 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) does not involve the recruitment of JAK2.Moreover, we determined that ANG II attenuated the insulin-stimulated phosphorylation of Akt at Ser473 in rat heart. This result agrees with previously reported observations. Whereas, 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.Based on our results, we postulate that ANG-(1-7) potentiates insulin action 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.