International Journal of Cardiology ( IF 3.5 ) Pub Date : 2021-12-02 , DOI: 10.1016/j.ijcard.2021.11.085 Takako Yao 1 , Tsutomu Fujimura 2 , Kimie Murayama 3 , Ko Okumura 4 , Yoshinori Seko 4
Background
Oxidative stress is implicated in the pathogenesis of doxorubicin-induced apoptosis in cardiac myocytes. However, the precise mechanism remains uncertain. We identified an apoptosis-inducing humoral factor, in a conditioned medium from cardiac myocytes subjected to hypoxia/reoxygenation, to be 69th tyrosine-sulfated eukaryotic translation initiation factor 5A (eIF5A). We named this novel secreted form of eIF5A, Oxidative stress-Responsive Apoptosis Inducing Protein (ORAIP). We confirmed that ischemia/reperfusion, ultraviolet-irradiation, and ionizing radiation significantly increased plasma levels of ORAIP in vivo, supporting that secretion of ORAIP is specific to the oxidative stress. To investigate the role of ORAIP in doxorubicin-induced apoptosis of cardiac myocytes.
Methods: We analyzed plasma levels of ORAIP in rats treated with doxorubicin (10 mg/Kg) in vivo, and the effects of neutralizing anti-ORAIP monoclonal antibody (mAb) on doxorubicin-induced apoptosis of cardiac myocytes in vitro.
Results: The (mean ± SE) plasma ORAIP levels before doxorubicin administration were (13.7 ± 2.7) ng/mL, they markedly increased with peak levels ([178.6 ± 6.5] ng/mL, p < 0.00001, vs. before administration) at 20 to 60 min after doxorubicin administration, then gradually decreased to (118.0 ± 4.8) ng/mL at 120 min. Treatment with a neutralizing anti-ORAIP mAb significantly (nearly 50%) suppressed doxorubicin-induced apoptosis of cardiac myocytes.
Conclusions: These data indicate that doxorubicin induces oxidative stress resulting in the strong expression of ORAIP in cardiac myocytes and marked secretion of ORAIP into peripheral circulation. This strongly suggests that ORAIP can be a novel sensitive biomarker as well as a possible therapeutic target for doxorubicin-induced cell injury in anti-cancer therapy.
中文翻译:
氧化应激反应性凋亡诱导蛋白 (ORAIP) 在阿霉素诱导的大鼠心肌细胞凋亡中起关键作用
背景
氧化应激与多柔比星诱导的心肌细胞凋亡的发病机制有关。然而,确切的机制仍然不确定。我们在经受缺氧/复氧的心肌细胞的条件培养基中鉴定出一种诱导细胞凋亡的体液因子是第 69 种酪氨酸硫酸化真核翻译起始因子 5A (eIF5A)。我们将这种新的 eIF5A 分泌形式命名为氧化应激反应性凋亡诱导蛋白 (ORAIP)。我们证实缺血/再灌注、紫外线照射和电离辐射显着增加体内 ORAIP 的血浆水平,支持 ORAIP 的分泌对氧化应激具有特异性。探讨ORAIP在阿霉素诱导的心肌细胞凋亡中的作用。
方法:我们在体内分析了用多柔比星(10 mg/Kg)处理的大鼠血浆ORAIP水平,以及体外中和抗ORAIP单克隆抗体(mAb)对多柔比星诱导的心肌细胞凋亡的影响。
结果:阿霉素给药前(平均值±标准差)血浆 ORAIP 水平为(13.7±2.7)ng/ mL ,在多柔比星给药后 20 至 60 分钟,然后在 120 分钟时逐渐降至 (118.0 ± 4.8) ng/mL。用中和抗 ORAIP mAb 治疗显着(接近 50%)抑制了阿霉素诱导的心肌细胞凋亡。
结论:这些数据表明,多柔比星诱导氧化应激,导致心肌细胞中 ORAIP 的强表达和 ORAIP 显着分泌到外周循环中。这有力地表明,ORAIP 可以成为一种新的敏感生物标志物,以及在抗癌治疗中多柔比星诱导的细胞损伤的可能治疗靶点。