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; Tsutomu Fujimura; Kimie Murayama; Ko Okumura; Yoshinori Seko

doi:10.3390/cells6040035

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

Cells. 2017 Oct 18;6(4):35. doi: 10.3390/cells6040035.

Authors

Takako Yao¹, Tsutomu Fujimura², Kimie Murayama³, Ko Okumura⁴, Yoshinori Seko⁵

Affiliations

¹ Division of Cardiovascular Medicine, Institute for Adult Diseases, Asahi Life Foundation, Tokyo 103-0002, Japan. apr16_taco@yahoo.co.jp.
² Laboratory of Bioanalytical Chemistry, Tohoku Medical and Pharmaceutical University, Sendai 981-0905, Japan. fujitsu@juntendo.ac.jp.
³ Division of Proteomics and Biomolecular Science, BioMedical Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan. murayama@juntendo.ac.jp.
⁴ Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan. kokumura@juntendo.ac.jp.
⁵ Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan. sekoyosh-tky@umin.ac.jp.

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.

Keywords: apoptosis; cardiac myocytes; diabetes mellitus (DM); high glucose; oxidative stress; oxidative stress-responsive apoptosis inducing protein (ORAIP); pancreatic β-cells.