Wan Qinggong, Xu Tao, Ding Wei, Zhang Xuejuan, Ji Xiaoyu, Yu Tao, Yu Wanpeng, Lin Zhijuan, Wang Jianxun
Center for Regenerative Medicine, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.
School of Basic Medical Sciences, Qingdao University, Qingdao, China.
Front Genet. 2019 Jan 21;9:734. doi: 10.3389/fgene.2018.00734. eCollection 2018.
Doxorubicin (DOX) is a broad-spectrum anti-tumor drug, but its cardiotoxicity limits its clinical application. A better understanding of the molecular mechanisms underlying DOX cardiotoxicity will benefit clinical practice and remedy heart failure. Our present study observed that DOX caused cardiomyocyte (H9c2) apoptosis via the induction of abnormal mitochondrial fission. Notably, the expression levels of p21 increased in DOX-treated cardiomyocytes, and the silencing of p21 using siRNA greatly attenuated mitochondrial fission and apoptosis in cardiomyocytes. We also found that miR-499-5p could directly target p21 and attenuated DOX-induced mitochondrial fission and apoptosis. The role of the miR-499-5p-p21 axis in the prevention of DOX cardiotoxicity was also validated in the mice model. DOX treatment induced an upregulation of p21, which induced subsequent abnormal mitochondrial fission and myocardial apoptosis in mouse heart. Adenovirus-harboring miR-499-5p-overexpressing mice exhibited significantly reduced p21 expression, mitochondrial fission and myocardial apoptosis in hearts following DOX administration. The miR-499-5p-overexpressing mice also exhibited improved cardiomyocyte hypertrophy and cardiac function after DOX treatment. However, miR-499-5p was not involved in the DOX-induced apoptosis of cancer cells. Taken together, these findings reveal an emerging role of p21 in the regulation of mitochondrial fission program. miR-499-5p attenuated mitochondrial fission and DOX cardiotoxicity via the targeting of p21. These results provide new evidence for the miR-499-5p-p21 axis in the attenuation of DOX cardiotoxicity. The development of new therapeutic strategies based on the miR-499-5p-p21 axis is a promising path to overcome DOX cardiotoxicity as a chemotherapy for cancer treatment.
阿霉素（DOX）是一种广谱抗肿瘤药物，但其心脏毒性限制了其临床应用。更好地了解DOX心脏毒性的分子机制将有助于临床实践并治疗心力衰竭。我们目前的研究观察到，DOX通过诱导异常的线粒体分裂导致心肌细胞（H9c2）凋亡。值得注意的是，DOX处理的心肌细胞中p21的表达水平升高，使用siRNA沉默p21可大大减轻心肌细胞中的线粒体分裂和凋亡。我们还发现miR-499-5p可以直接靶向p21并减轻DOX诱导的线粒体分裂和凋亡。miR-499-5p-p21轴在预防DOX心脏毒性中的作用也在小鼠模型中得到了验证。DOX处理诱导小鼠心脏中p21上调，进而导致随后的异常线粒体分裂和心肌凋亡。携带腺病毒的miR-499-5p过表达小鼠在给予DOX后，心脏中p21表达、线粒体分裂和心肌凋亡显著降低。miR-499-5p过表达小鼠在DOX处理后还表现出心肌细胞肥大和心脏功能改善。然而，miR-499-5p不参与DOX诱导的癌细胞凋亡。综上所述，这些发现揭示了p21在调节线粒体分裂程序中的新作用。miR-499-5p通过靶向p21减轻线粒体分裂和DOX心脏毒性。这些结果为miR-499-5p-p21轴减轻DOX心脏毒性提供了新证据。基于miR-499-5p-p21轴开发新的治疗策略是克服DOX心脏毒性作为癌症化疗的一条有前途的途径。
