Yao Takako, Fujimura Tsutomu, Murayama Kimie, Okumura Ko, Seko Yoshinori
Division of Cardiovascular Medicine, Institute for Adult Diseases, Asahi Life Foundation, Tokyo 103-0002, Japan.
Laboratory of Bioanalytical Chemistry, Tohoku Medical and Pharmaceutical University, Sendai 981-0905, Japan.
Cells. 2017 Oct 18;6(4):35. doi: 10.3390/cells6040035.
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.
我们之前在缺氧/复氧心肌细胞的条件培养基中鉴定出一种新型的凋亡诱导体液因子。我们将这种经翻译后修饰的真核翻译起始因子5A的新型分泌形式命名为氧化应激反应性凋亡诱导蛋白（ORAIP）。我们证实，心肌缺血/再灌注显著提高了血浆ORAIP水平，并且在体内，中和抗ORAIP单克隆抗体（mAb）可明显抑制大鼠心肌缺血/再灌注损伤。在本研究中，为了探究糖尿病（DM）中心肌细胞和胰腺β细胞的细胞损伤机制，我们分析了DM模型大鼠的血浆ORAIP水平以及ORAIP在体外高糖诱导的心肌细胞凋亡中的作用。我们还检测了重组ORAIP是否能诱导胰腺β细胞凋亡。与非糖尿病阶段相比，糖尿病大鼠糖尿病阶段的血浆ORAIP水平升高了约18倍。高糖诱导心肌细胞大量凋亡（66.2±2.2%），体外中和抗ORAIP mAb可抑制78%的凋亡。此外，重组ORAIP在体外能明显诱导胰腺β细胞凋亡。这些发现强烈表明，ORAIP在DM的高血糖诱导的心肌损伤和胰腺β细胞损伤中起关键作用。ORAIP将成为心脏损伤和DM自身进展的生物标志物及关键治疗靶点。
