Angiotensin-(1-7) improves insulin signal transduction and inhibits growth-promoting signaling pathways in heart of fructose-fed rats

JF GIANI; MC MUÑOZ; MA MAYER; V BURGHI; D TURYN; FP DOMINICI

Washington, EEUU

Congreso; The Endocrine Society's 91st Annual Meeting; 2009

Title: Angiotensin-(1-7) improves insulin signal transduction and inhibits growth-promoting signaling pathways in heart of fructose-fed ratsJF Giani1, MC Muñoz1, MA Mayer1, V Burghi1, D Turyn1 and FP Dominici1. 1IQUIFIB - School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina, 1113. BackgroundAlterations within the renin-angiotensin system (RAS) are an important contributor to the development of insulin resistance (1) and cardiac hypertrophy (2). The RAS is composed of two arms. The first arm is represented by angiotensin (Ang) II which contributes to the development of insulin resistance in several tissues and leads to cardiac remodeling by inducing the activation of several molecules, including ERK1/2 and RhoA kinase. The second arm is antihypertensive and antihypertrophic, where the major participant is Ang-(1-7), an heptapeptide that constitutes an important functional end-product of the RAS (3). Accordingly, in the present study we examined whether chronic treatment with Ang-(1-7) restores insulin signaling and inhibits growth-promoting pathways in fructose-fed rats, an animal model of insulin resistance with elevated circulating levels of Ang II (4). MethodsSix-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water (FFR). For the last 2 weeks of a 6-week period of either diet, control and FFR where implanted with subcutaneous osmotic pumps that delivered Ang-(1-7) (100ng.kg-1.min-1). A subgroup of each group of animals (control or FFR) underwent a sham surgery. By immunoblotting, we evaluate insulin signaling through the insulin receptor (IR)/IR substrate (IRS)-1/phosphatidylinositol-3 kinase (PI3K)/Akt pathway after an acute administration of insulin via vena cava. To further evaluate the activation of growth-promoting enzymes, basal phosphorylation levels of ERK1/2 and RhoA were also determined by immunoblotting. ResultsFFR displayed higher circulating levels of Ang II, as measured by RIA, that remained unaltered after Ang-(1-7) treatment.An impairment in all steps of insulin signaling analyzed IR, IRS-1, p85-IRS-1 association and Akt phosphorylation (53 ,63 ,68 and 55% of control values respectively) was detected in heart after acute insulin stimulation. Interestingly, significant improvement in this pathway was detected after Ang-(1-7) treatment.FFR showed a significant increase in phospho-ERK1/2 and phospho-RhoA levels (1.9 and 2.5 fold increase over control values respectively) which decreased significantly after Ang-(1-7) treatment.ConclusionChronic Ang-(1-7) treatment resulted in a restoration of insulin signaling through the IR/IRS-1/PI3K/Akt pathway and attenuated the growth-promoting pathways in the heart, without affecting Ang II plasma levels.References: (1) Henriksen EJ et al., Am J Physiol Regulatory Integrative Comp Physiol 2007; 293:R974(2) Mehta PK et al., Am J Physiol Cell Physiol 2007; 292:C82(3) Ferrario CM et al., Am J Physiol Heart Circ Physiol 2005; 289:H2281(4) Kobayashi R et al., Hypertension 1993; 21:1051