Oxidative Stress-Responsive Apoptosis Inducing Protein (ORAIP) Plays a Critical Role in High Glucose-Induced Apoptosis in Rat Cardiac Myocytes and Murine Pancreatic β-Cells.

Takako Yao,Yoshinori Seko,Kimie Murayama,Tsutomu Fujimura,Ko Okumura

doi:10.3390/cells6040035

Abstract

We previously identified a novel apoptosis-inducing humoral factor in the conditioned medium of hypoxic/reoxygenated-cardiac myocytes. We named this novel post-translationally-modified secreted-form of eukaryotic translation initiation factor 5A Oxidative stress-Responsive Apoptosis-Inducing Protein (ORAIP). We confirmed that myocardial ischemia/reperfusion markedly increased plasma ORAIP levels and rat myocardial ischemia/reperfusion injury was clearly suppressed by neutralizing anti-ORAIP monoclonal antibodies (mAbs) in vivo. In this study, to investigate the mechanism of cell injury of cardiac myocytes and pancreatic β-cells involved in diabetes mellitus (DM), we analyzed plasma ORAIP levels in DM model rats and the role of ORAIP in high glucose-induced apoptosis of cardiac myocytes in vitro. We also examined whether recombinant-ORAIP induces apoptosis in pancreatic β-cells. Plasma ORAIP levels in DM rats during diabetic phase were about 18 times elevated as compared with non-diabetic phase. High glucose induced massive apoptosis in cardiac myocytes (66.2 ± 2.2%), which was 78% suppressed by neutralizing anti-ORAIP mAb in vitro. Furthermore, recombinant-ORAIP clearly induced apoptosis in pancreatic β-cells in vitro. These findings strongly suggested that ORAIP plays a pivotal role in hyperglycemia-induced myocardial injury and pancreatic β-cell injury in DM. ORAIP will be a biomarker and a critical therapeutic target for cardiac injury and progression of DM itself.

Highlights

Cardiovascular injury involved in diabetes mellitus (DM) is known to be mainly due to coronary artery disease with myocardial ischemia/reperfusion as well as direct metabolic cardiac myocyte injury by hyperglycemia. oxidative stress has been implicated in both mechanisms, the precise mechanism of the latter remains unclear
We previously identified a novel apoptosis-inducing humoral factor, in a conditioned medium from cardiac myocytes subjected to hypoxia/reoxygenation, to be tyrosine-sulfated and more hypusinated secreted form of eukaryotic translation initiation factor 5A [1]
We confirmed that Oxidative stress-Responsive ApoptosisInducing Protein (ORAIP) is secreted in response to the oxidative stresses including ischemia/reperfusion, hypoxia/reoxygenation, ultraviolet-irradiation, ionizing radiation, cold/warm-stress, and blood acidification [1,2], acts as a pro-apoptotic ligand to induce apoptosis in target cells such as cardiac myocytes. In addition to these acute oxidative stresses, we found that the plasma levels of ORAIP were markedly elevated in patients with chronic diseases such as chronic kidney disease and atrial fibrillation in which oxidative stress plays a critical role in the pathogenesis involved [3,4]

Summary

Introduction

Cardiovascular injury involved in DM is known to be mainly due to coronary artery disease with myocardial ischemia/reperfusion as well as direct metabolic cardiac myocyte injury by hyperglycemia. oxidative stress has been implicated in both mechanisms, the precise mechanism of the latter remains unclear. We previously identified a novel apoptosis-inducing humoral factor, in a conditioned medium from cardiac myocytes subjected to hypoxia/reoxygenation, to be tyrosine-sulfated and more hypusinated secreted form of eukaryotic translation initiation factor 5A (eIF5A) [1]. The apoptosis of cardiac myocytes induced by hypoxia/reoxygenation was suppressed by anti-eIF5A neutralizing mAbs in vitro. In vivo treatment with anti-eIF5A neutralizing mAbs significantly reduced myocardial ischemia/reperfusion injury. These results demonstrated that a novel post-translationally modified secreted form of eIF5A is a specific biomarker and a critical therapeutic target for oxidative stress-induced cell injury. We named this novel tyrosine-sulfated secreted form of eIF5A Oxidative stress-Responsive Apoptosis Inducing

Objectives

Methods

Results

Conclusion