Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1β/ErbB in response to myocardial infarction resulting in worsening heart failure

Oghenerukevwe Odiete,Michael F Hill,Ewa A Konik,Douglas B Sawyer

doi:10.1186/1475-2840-12-52

Oghenerukevwe Odiete, Michael F Hill + Show 2 more

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https://doi.org/10.1186/1475-2840-12-52

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Abstract

BackgroundDiabetes mellitus (DM) patients surviving myocardial infarction (MI) exhibit a substantially higher incidence of subsequent heart failure (HF). Neuregulin (NRG)-1 and erythroblastic leukemia viral oncogene homolog (ErbB) receptors have been shown to play a critical role in maintenance of cardiac function. However, whether myocardial NRG-1/ErbB is altered during post-MI HF associated with DM remains unknown. The aim of this study was to determine the impact of type 1 DM on the myocardial NRG-1/ErbB system following MI in relation to residual left ventricular (LV) function.MethodsType 1 DM was induced in rats via administration of streptozotocin (65 mg/kg, i.p.). Control rats were injected with citrate buffer (vehicle) only. Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by ligation of the left coronary artery. Sham MI rats underwent the same surgical procedure with the exception that the left coronary artery was not ligated. At 4 weeks after surgery, residual in vivo LV function was assessed via echocardiography. Myocardial protein expression of NRG-1β, ErbB2 and ErbB4 receptors, and MDM2 (a downstream signaling pathway induced by NRG-1 that has been implicated in cell survival) was assessed in the remaining, viable LV myocardium by Western blotting. Changes in ErbB receptor localization in the surviving LV myocardium of diabetic and non-diabetic post-MI rats was determined using immunohistochemistry techniques.ResultsAt 4 weeks post-MI, echocardiography revealed that LV fractional shortening (FS) and LV ejection fraction (EF) were significantly lower in the DM + MI group compared to the MI group (LVFS: 17.9 ± 0.7 vs. 25.2 ± 2.2; LVEF: 35.5 ± 1.4 vs. 47.5 ± 3.5, respectively; P < 0.05), indicating an increased functional severity of HF among the DM + MI rats. Up-regulation of NRG-1β and ErbB2 protein expression in the MI group was abrogated in the DM + MI group concurrent with degradation of MDM2, a downstream negative regulator of p53. ErbB2 and ErbB4 receptors re-localized to cardiac myocyte nuclei in failing type 1 diabetic post-MI hearts.ConclusionsType 1 DM prevents compensatory up-regulation of myocardial NRG-1/ErbB after MI coincident with an increased severity of HF.

Highlights

Diabetes mellitus (DM) patients surviving myocardial infarction (MI) exhibit a substantially higher incidence of subsequent heart failure (HF)
Using a rat model of HF due to MI by coronary ligation in the presence of STZ-induced DM, a type 1 model, we assessed the protein expression profiles of NRG-1β, ErbB2 and ErbB4 receptors, murine double minute 2 (MDM2), as well as changes in Erythroblastic leukemia viral oncogene homolog (ErbB) receptor localization in the surviving left ventricular (LV) myocardium of diabetic post-MI rats in relation to residual LV function
Blood glucose levels were significantly elevated in the DM and DM + MI groups of rats compared with the non-diabetic animal groups (Table 1)

Summary

Introduction

Diabetes mellitus (DM) patients surviving myocardial infarction (MI) exhibit a substantially higher incidence of subsequent heart failure (HF). Neuregulin (NRG)-1 and erythroblastic leukemia viral oncogene homolog (ErbB) receptors have been shown to play a critical role in maintenance of cardiac function. Whether myocardial NRG-1/ErbB is altered during post-MI HF associated with DM remains unknown. Diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher cardiovascular morbidity and mortality than those without DM [1]. Neuregulin (NRG)-1, along with the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases through which NRG-1 ligands signal, have been shown to play an essential role in cardiac development [4,5] and maintenance of the adult heart [6]. Endothelium-selective deletion of NRG-1 has been demonstrated to worsen post-ischemic contractile recovery after coronary artery ligation [10]

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