Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity in mice
Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity in mice
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DOI：
10.1016/j.freeradbiomed.2020.10.303
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发表时间：
2021-02-13
影响因子：
7.4
通讯作者：
Yoshimura, Michihiro
中科院分区：
文献类型：
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作者：
Tanaka, Yoshiro;Nagoshi, Tomohisa;Yoshimura, Michihiro
越来越多的证据表明，高血清尿酸（UA）与左心室功能障碍（LV）有关。虽然黄嘌呤氧化酶（XO）激活是ATP和嘌呤降解的终末步骤的关键调节机制，但心脏组织XO在LV功能障碍中的病理生理作用仍不清楚。我们在本文中研究了组织XO活性在阿霉素诱导的心脏毒性中的作用和功能意义。将多柔比星（10 mg/kg）或溶媒以单次注射方式腹膜内给药至小鼠。在多柔比星注射前24小时开始，用或不用口服XO抑制剂（非布司他3 mg/kg/天或托匹司他5 mg/kg/天）处理小鼠8天。心脏组织XO活性测定一个高度敏感的液相色谱/质谱分析和心脏UA含量显着增加阿霉素治疗的小鼠在第7天，显着减少XO抑制剂。因此，XO抑制剂显著改善了多柔比星给药损害的LV射血分数（通过超声心动图评估）和LV发展压力（通过离体Langendorff心脏灌注评估）。这与XO衍生的过氧化氢产生的增加有关，伴随着凋亡和铁蛋白途径的上调，所有这些都被XO抑制剂减少。此外，代谢组学分析显示，阿霉素治疗的心脏嘌呤代谢增强，XO抑制剂抑制了次黄嘌呤-黄嘌呤-UA的系列代谢反应，ATP和嘌呤降解的途径。总之，多柔比星给药诱导与LV功能受损相关的心脏组织XO活化。XO抑制剂通过抑制XO衍生的氧化应激和细胞死亡信号以及维持与嘌呤代谢途径调节相关的心脏能量代谢来减弱阿霉素诱导的心脏毒性。
Accumulating evidence suggests that high serum uric acid (UA) is associated with left ventricular (LV) dysfunction. Although xanthine oxidase (XO) activation is a critical regulatory mechanism of the terminal step in ATP and purine degradation, the pathophysiological role of cardiac tissue XO in LV dysfunction remains unclear. We herein investigated the role and functional significance of tissue XO activity in doxorubicin-induced cardiotoxicity. Either doxorubicin (10 mg/kg) or vehicle was intraperitonially administered in a single injection to mice. Mice were treated with or without oral XO-inhibitors (febuxostat 3 mg/kg/day or topimxostat 5 mg/kg/ day) for 8 days starting 24 h before doxorubicin injection. Cardiac tissue XO activity measured by a highly sensitive assay with liquid chromatography/mass spectrometry and cardiac UA content were significantly increased in doxorubicin-treated mice at day 7 and dramatically reduced by XO-inhibitors. Accordingly, XO-inhibitors substantially improved LV ejection fraction (assessed by echocardiography) and LV developed pressure (assessed by ex vivo Langendorff heart perfusion) impaired by doxorubicin administration. This was associated with an increase in XO-derived hydrogen peroxide production with concomitant upregulation of apoptotic and ferroptotic pathways, all of which were reduced by XO-inhibitors. Furthermore, metabolome analyses revealed enhanced purine metabolism in doxorubicin-treated hearts, and XO-inhibitors suppressed the serial metabolic reaction of hypoxanthine-xanthine-UA, the paths of ATP and purine degradation. In summary, doxorubicin administration induces cardiac tissue XO activation associated with impaired LV function. XO-inhibitors attenuate doxorubicin-induced cardiotoxicity through inhibition of XO-derived oxidative stress and cell death signals as well as the maintenance of cardiac energy metabolism associated with modulation of the purine metabolic pathway.