Activation of EGFR/ERBB2 via Pathways Involving ERK1/2, P38 MAPK, AKT and FOXO Enhances Recovery of Diabetic Hearts from Ischemia-Reperfusion Injury

Saghir Akhtar,Ibrahim F Benter,Bindu Chandrasekhar,Mariam H M Yousif,Ferenc Gallyas

doi:10.1371/journal.pone.0039066

Saghir Akhtar, Ibrahim F Benter + Show 3 more

Open Access

https://doi.org/10.1371/journal.pone.0039066

Copy DOI

Journal: PLoS ONE	Publication Date: Jun 13, 2012
Citations: 78	License type: CC BY 4.0

Affiliation: Kuwait University

Abstract

This study characterized the effects of diabetes and/or ischemia on epidermal growth factor receptor, EGFR, and/or erbB2 signaling pathways on cardiac function. Isolated heart perfusion model of global ischemia was used to study the effect of chronic inhibition or acute activation of EGFR/erbB2 signaling on cardiac function in a rat model of type-1 diabetes. Induction of diabetes with streptozotocin impaired recovery of cardiac function (cardiac contractility and hemodynamics) following 40 minutes of global ischemia in isolated hearts. Chronic treatment with AG825 or AG1478, selective inhibitors of erbB2 and EGFR respectively, did not affect hyperglycemia but led to an exacerbation whereas acute administration of the EGFR ligand, epidermal growth factor (EGF), led to an improvement in cardiac recovery in diabetic hearts. Diabetes led to attenuated dimerization and phosphorylation of cardiac erbB2 and EGFR receptors that was associated with reduced signaling via extracellular-signal-regulated kinase 1/2 (ERK1/2), p38 mitogen activated protein (MAP) kinase and AKT (protein kinase B). Ischemia was also associated with reduced cardiac signaling via these molecules whereas EGF-treatment opposed diabetes and/or ischemia induced changes in ERK1/2, p38 MAP kinase, and AKT-FOXO signaling. Losartan treatment improved cardiac function in diabetes but also impaired EGFR phosphorylation in diabetic heart. Co-administration of EGF rescued Losartan-mediated reduction in EGFR phosphorylation and significantly improved cardiac recovery more than with either agent alone. EGFR/erbB2 signaling is an important cardiac survival pathway whose activation, particularly in diabetes, ischemia or following treatment with drugs that inhibit this cascade, significantly improves cardiac function. These findings may have clinical relevance particularly in the treatment of diabetes-induced cardiac dysfunction.

Highlights

Diabetes significantly increases the risk of cardiovascular disease by 3- to 8-fold [1]
The major novel finding of this study is that diabetes is associated with a reduction in epidermal growth factor receptor (EGFR)/erbB2 heterodimer signaling in the heart and that activation of EGFR/erbB2 signaling via epidermal growth factor (EGF) leads to markedly improved cardiac recovery from I/R by opposing diabetes and/or ischemia induced changes in ERK1/ 2, p38 mitogen activated protein (MAP) kinase, AKT and FOXO signaling
This study showed that the relative improvements in cardiac function with EGF were similar to those observed with a clinically established AT1 receptor antagonist, Losartan

Summary

Introduction

Diabetes significantly increases the risk of cardiovascular disease by 3- to 8-fold [1]. It is becoming clear that signal transduction changes induced during hyperglycemia are not always reversed by current therapies designed to lower glucose levels and will need to be normalized for effective treatment of diabetes complications. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases comprises four members: EGFR (erbB1), EGFR2 (erbB2, Neu, HER2), EGFR3 (erbB3) and EGFR4 (erbB4) Of these EGFR is a 175-kDa glycoprotein that can be activated by several different ligands including epidermal growth factor (EGF), heparin-binding EGF (HB-EGF), amphiregulin and betacellulin [3] to induce either homodimerization or heterodimerization with other EGFR family members, most notably erbB2 which is the preferred partner for dimerization. The erbB2 receptor lacks a ligand binding domain and relies on dimerization with other EGFR family members for signaling. EGFR transactivation can occur via G-protein coupled receptors (GPCR), such as angiotensin II (Ang II) and endothelin [6]

Methods

Results

Conclusion