Zhang Siqi, Fan Yixin, Zheng Binbin, Wang Yu, Miao Chen, Su Yue, Li Kun, E Yan, Wang Xueli, He Xueming, Wu Xuefeng, Xu Chenjie, Tang Yulin, Liu Wen-Tao, Kong Xiangqing, Hu Liang
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
Front Pharmacol. 2022 Apr 25;13:828890. doi: 10.3389/fphar.2022.828890. eCollection 2022.
Doxorubicin induces severe cardiotoxicity, accompanied by the high level of bilirubin in the blood. The conventional wisdom is that bilirubin is considered as a marker of liver damage. By contrast, here we aim to explore the potential protective effect of bilirubin on doxorubicin-induced cardiotoxicity, and investigate the mechanism for drug development. Doxorubicin was used to establish cardiotoxicity model and . The electrocardiogram (ECG), echocardiography and molecular biological methods were used to detect the effects of bilirubin on doxorubicin-induced cardiotoxicity. Consecutive intraperitoneal injection of bilirubin for 7 days significantly attenuated doxorubicin-induced arrhythmia, prolonged survival time and reduced the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) and α-hydroxybutyrate dehydrogenase (α-HBDH) in mice. Bilirubin also markedly inhibited doxorubicin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and connexin 43 (Cx43), and improved gap junction function and . In addition, bilirubin activated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and induced suppressor of cytokine signaling 3 (SOCS3) expression, which was abolished by Axl inhibition. Moreover, pretreatment with AMPK agonist or AMPK inhibitor could mimic or abolish the cardioprotective effect of bilirubin on H9C2 cells , respectively. Altogether, bilirubin upregulates gap junctions' function to protect against doxorubicin-induced cardiotoxicity by activating AMPK-Axl-SOCS3 signaling axis. We enrich the physiological function of bilirubin, and provide theoretical support for drug development.
阿霉素会引发严重的心脏毒性，并伴有血液中胆红素水平升高。传统观点认为胆红素被视为肝损伤的标志物。相比之下，我们旨在探索胆红素对阿霉素诱导的心脏毒性的潜在保护作用，并研究其作用机制以用于药物研发。使用阿霉素建立心脏毒性模型。采用心电图（ECG）、超声心动图和分子生物学方法来检测胆红素对阿霉素诱导的心脏毒性的影响。连续7天腹腔注射胆红素可显著减轻阿霉素诱导的心律失常，延长存活时间，并降低小鼠体内天冬氨酸转氨酶（AST）、乳酸脱氢酶（LDH）、肌酸激酶同工酶MB（CK-MB）和α-羟丁酸脱氢酶（α-HBDH）的水平。胆红素还显著抑制阿霉素诱导的c-Jun氨基末端激酶（JNK）和连接蛋白43（Cx43）的磷酸化，并改善缝隙连接功能。此外，胆红素激活了5'-单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）并诱导细胞因子信号转导抑制因子3（SOCS3）表达，而Axl抑制可消除这种作用。此外，用AMPK激动剂或AMPK抑制剂预处理可分别模拟或消除胆红素对H9C2细胞的心脏保护作用。总之，胆红素通过激活AMPK-Axl-SOCS3信号轴上调缝隙连接功能，以保护心脏免受阿霉素诱导的心脏毒性。我们丰富了胆红素的生理功能，并为药物研发提供了理论支持。
