Angiotensin‐(1‐7) inhibits epidermal growth factor receptor transactivation via a Mas receptor‐dependent pathway

Abstract

BACKGROUND AND PURPOSEThe transactivation of the epidermal growth factor (EGF) receptor appears to be an important central transduction mechanism in mediating diabetes-induced vascular dysfunction. Angiotensin-(1-7) [Ang-(1-7)] via its Mas receptor can prevent the development of hyperglycaemia-induced cardiovascular complications. Here, we investigated whether Ang-(1-7) can inhibit hyperglycaemia-induced EGF receptor transactivation and its classical signalling via ERK1/2 and p38 MAPK in vivo and in vitro. EXPERIMENTAL APPROACHStreptozotocin-induced diabetic rats were chronically treated with Ang-(1-7) or AG1478, a selective EGF receptor inhibitor, for 4 weeks and mechanistic studies performed in the isolated mesenteric vasculature bed as well as in primary cultures of vascular smooth muscle cells (VSMCs). KEY RESULTSDiabetes significantly enhanced phosphorylation of EGF receptor at tyrosine residues Y992, Y1068, Y1086, Y1148, as well as ERK1/2 and p38 MAPK in the mesenteric vasculature bed whereas these changes were significantly attenuated upon Ang-(1-7) or AG1478 treatment. In VSMCs grown in conditions of high glucose (25 mM), an Src-dependent elevation in EGF receptor phosphorylation was observed. Ang-(1-7) inhibited both Ang II-and glucose-induced transactivation of EGF receptor. The inhibition of high glucose-mediated Src-dependant transactivation of EGF receptor by Ang-(1-7) could be prevented by a selective Mas receptor antagonist, D-Pro7-Ang-(1-7). CONCLUSIONS AND IMPLICATIONSThese results show for the first time that Ang-(1-7) inhibits EGF receptor transactivation via a Mas receptor/Src-dependent pathway and might represent a novel general mechanism by which Ang-(1-7) exerts its beneficial effects in many disease states including diabetes-induced vascular dysfunction.

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…In proximal tubular cells, Ang II-stimulated phosphorylation of three MAP kinases (p38, ERK1/2 and c-Jun) was also inhibited by Ang-(1-7), an effect that was also completely blocked by the Mas antagonist A-779 (Su et al 2006). Furthermore, a Mas-dependent inhibition of Ang IIinduced EGFR transactivation by Ang-(1-7) has also been demonstrated in rat VSMCs (Akhtar et al 2012).…”

Modulation of the action of insulin by angiotensin-(1–7)

“…Prevention of diabetes-induced abnormal vascular responsiveness to noradrenaline, endothelin-1, AngII, carbachol and histamine in the mesenteric bed, isolated carotid and renal arteries [173]; increased LV-developed pressure and serum nitrite/nitrate and decreased LV mass/body mass and LV collagen content [174]; AVE-0991 rescued cardiac function under diabetic conditions as indicated by a normalization of blood pressure and contractility parameters [175]; and Ang-(1-7) inhibited EGF receptor transactivation via a Mas receptor/Src-dependent pathway, indicating that activation of the EGF receptor is a key player in mediating diabetes-induced vascular dysfunction [177] Chronic infusion of XNT (ACE2 activator) on STZ-induced diabetic rats Improved endothelium-dependent vasorelaxation of aortic rings; effect blocked by A-779 [176] Deletion of ACE2 in diabetic Akita mice…”

“…In general these studies imply a cardioprotective role for Ang-(1-7) under hyperglycaemic conditions and point to new therapeutic strategies using Ang-(1-7) agonists to treat the cardiovascular complications associated with diabetes mellitus. A potential mechanism involved in these beneficial effects of Ang-(1-7) could be related to its ability to inhibit EGF (epidermal growth factor) receptor transactivation via a Mas receptor-dependent pathway [177]. In addition, an indirect role for this cardioprotective role of Ang-(1-7) has been demonstrated by deletion of the Ace2 gene in diabetic Akita mice.These animals displayed increased plasma and tissue AngII, impaired systolic and diastolic function, and increased NADPH oxidase activity and greater oxidative stress in the heart [178].…”

RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes

“…Thus, targeting EGFR inhibition with MR antagonists such as RU may have beneficial and detrimental consequences in the heart and thus their net therapeutic advantage will depend on the relative importance or contributions of these different EGFR-driven mechanisms in a given pathological state. Indeed, we have recently shown that by removing the EGFR inhibitory effects of Los, which blocks Ang II-mediated transactivation of EGFR, by coadministering an EGFR ligand, significant improvement in cardiac function over that achieved by Los alone was attained [40]. …”