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.
Int J Cardiol. 2022 Feb 1;348:119-124. doi: 10.1016/j.ijcard.2021.11.085. Epub 2021 Dec 2.
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.
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.
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.
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.
氧化应激与阿霉素诱导的心肌细胞凋亡的发病机制有关。然而，确切的机制尚不清楚。我们从经历缺氧/复氧的心肌细胞的条件培养基中鉴定出一种诱导凋亡的体液因子，为 69 位酪氨酸硫酸化的真核翻译起始因子 5A（eIF5A）。我们将这种新型分泌形式的 eIF5A 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著增加了体内 ORAIP 的血浆水平，支持 ORAIP 的分泌是氧化应激的特异性。为了研究 ORAIP 在阿霉素诱导的心肌细胞凋亡中的作用。
我们分析了体内给予阿霉素（10mg/kg）的大鼠的血浆 ORAIP 水平，以及中和抗 ORAIP 单克隆抗体（mAb）对体外阿霉素诱导的心肌细胞凋亡的影响。
阿霉素给药前（13.7±2.7）ng/ml 的平均±标准误差血浆 ORAIP 水平，给药后 20 至 60 分钟内显著增加至峰值水平（[178.6±6.5]ng/ml，p<0.00001，与给药前相比），然后逐渐下降至 120 分钟时的（118.0±4.8）ng/ml。用中和抗 ORAIP mAb 处理可显著（近 50%）抑制阿霉素诱导的心肌细胞凋亡。
这些数据表明，阿霉素诱导氧化应激导致心肌细胞中 ORAIP 的强烈表达和 ORAIP 向周围循环的大量分泌。这强烈表明，ORAIP 可以作为一种新型的敏感生物标志物，以及一种可能的治疗靶点，用于抗癌治疗中的阿霉素诱导的细胞损伤。
