Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, PR China.
Department of Emergency, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, PR China.
Biochem Biophys Res Commun. 2020 Jan 8;521(2):485-491. doi: 10.1016/j.bbrc.2019.10.140. Epub 2019 Oct 31.
Oxidative stress and cardiomyocyte apoptosis contributed to the progression of doxorubicin (Dox)-induced cardiotoxicity. Recent studies identified microRNA-22 (miR-22) as a cardiac- and skeletal muscle-enriched microRNA that functioned as a key regulator in stress-induced cardiac injury. The present study aimed to investigate the role and possible mechanism of miR-22 on Dox-induced oxidative stress and cardiomyocyte apoptosis. Mice were exposed to reduplicative injections of Dox (i.p., 4 mg/kg) weekly for consecutive 4 weeks to generate Dox-induced cardiotoxicity. Herein, we found that miR-22 level was significantly increased in murine hearts subjected to chronic Dox treatment. MiR-22 inhibition attenuated oxidative stress and cardiomyocyte apoptosis in vivo and in vitro, thereby preventing Dox-induced cardiac dysfunction. Mechanistically, we observed that miR-22 directly bound to the 3'-UTR of Sirt1 and caused SIRT1 downregulation. Conversely, miR-22 antagomir upregulated SIRT1 expression and SIRT1 inhibitor abolished the beneficial effects of miR-22 antagomir. In conclusion, miR-22 inhibition prevented oxidative stress and cardiomyocyte apoptosis via upregulating SIRT1 and miR-22 might be a new target for treating Dox-induced cardiotoxicity.
氧化应激和心肌细胞凋亡导致阿霉素（Dox）诱导的心脏毒性进展。最近的研究确定了 microRNA-22（miR-22）作为一种富含心脏和骨骼肌的 microRNA，作为应激诱导的心脏损伤的关键调节剂发挥作用。本研究旨在探讨 miR-22 在 Dox 诱导的氧化应激和心肌细胞凋亡中的作用及可能的机制。将小鼠每周重复接受 4mg/kg 的 Dox（腹腔内注射）连续 4 周，以产生 Dox 诱导的心脏毒性。在此，我们发现慢性 Dox 处理后的小鼠心脏中 miR-22 水平显著增加。miR-22 抑制可减轻体内和体外的氧化应激和心肌细胞凋亡，从而防止 Dox 诱导的心脏功能障碍。在机制上，我们观察到 miR-22 直接与 Sirt1 的 3'-UTR 结合，导致 SIRT1 下调。相反，miR-22 反义寡核苷酸上调 SIRT1 表达，而 SIRT1 抑制剂消除了 miR-22 反义寡核苷酸的有益作用。总之，miR-22 抑制通过上调 SIRT1 来防止氧化应激和心肌细胞凋亡，miR-22 可能是治疗 Dox 诱导的心脏毒性的新靶点。
