Abstract 443: α 1 -adrenergic Receptor Agonists Activate Akt Signalling via the Insulin Receptor Family of Receptors

Abstract

Introduction: Akt signalling was delineated in the context of insulin stimulation and is cardioprotective. Akt is activated by insulin or insulin-like growth factor 1 (IGF1), acting through their receptors (IRs, IGF1Rs). Other receptors including α 1 -adrenergic receptors (α 1 ARs) activate Akt, but the mechanism is unclear. Hypothesis: We hypothesise that α 1 -ARs activate Akt via insulin receptor family receptors (InsRFs). Our aims were to establish if this is so, and if linsitinib [a highly selective inhibitor of InsRFs developed for cancer] affects cardiac responses to α 1 -AR agonists. Methods: Rat neonatal cardiomyocytes were exposed to or adult rat hearts perfused with α 1 AR agonists [50 nM A61603; 100 μM phenylephrine (PE)] with/without linsitinib. Effects on signalling were assessed by immunoblotting. Protein synthesis was assessed using 3 H-Phe. Effects of linsitinib (2 mg/kg/d) on cardiac function/hypertrophy induced by PE (40 mg/kg/d, 4 d) in mice (male C57Bl6; 10 wks) in vivo were determined. Echocardiography was used to assess cardiac function and pulmonary/aortic flow. Results: We identified a third InsRF in heart, the insulin receptor-related receptor (IRR). IRRs are alkali-sensitive and required for pH regulation in kidney. Alkaline pH (pH 9.0) activated IRRs and Akt, and increased protein synthesis in perfused hearts, being activated in a complex with IR/IGF1Rs. α 1 ARs activated Akt in cardiomyocytes and perfused hearts and increased protein synthesis. Linsitinib inhibited activation of Akt and the increase in protein synthesis induced by alkaline pH or α 1 AR agonists. Thus, α 1 ARs signal via InsRFs to Akt and protein synthesis. In perfused hearts, linsitinib enhanced the increase in developed pressure induced by A61603 and, in vivo, linsitinib enhanced PE-induced left ventricular (LV) hypertrophy with increased LV wall thickness and decreased internal diameter. Aortic flow was compromised in the presence of PE/linsitinib. Conclusions: Our data demonstrate a novel signalling paradigm in which α 1 -ARs signal through one or more InsRFs in cardiomyocytes to activate Akt and increase protein synthesis. However, functionally, the InsRF signal appears to mitigate some of the hypertrophic effects of α 1 -AR signalling in the whole heart.