Department of Cardiovascular Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China; Electrocardiogram Room, Jiangxi Cancer Hospital, Nanchang, 330029, Jiangxi, China.
College of Pharmacy, Jiangxi University of Traditional Chinese Medicine & Jiangxi Cancer Hospital, 330004, Jiangxi, China.
Biomed Pharmacother. 2020 Mar;123:109751. doi: 10.1016/j.biopha.2019.109751. Epub 2020 Jan 17.
Doxorubicin (DOX), a wide-spectrum chemotherapeutic agent, is recognized to have cardiotoxic side effects when it is applied in hematological diseases and solid tumor management. However, the mechanisms behind the DOX-induced anomaly of vascular homeostasis remain mostly elusive. qRT-PCR and immumohistochemical staining indicated cardiac increase of miR-526b-3p, and decrease of CD31 and CD34 in DOX-treated mice. The regulatory function of miR-526b-3p on cardiac function and cardiac microvessel density was detected via the transfection of miR-526b-3p mimics or inhibitor into Human Umbilical Vein Endothelial Cells (HUVECs) and the administration of rAAV in mice. HUVECs proliferation, apoptosis, tube formation, and migration were inspected by EdU, flow cytometry, tube formation and transwell assays. MiR-526b-3p was anti-proliferative but apoptosis-initiating in HUVECs, and aggravated cardiac abnormalities caused by DOX. Mechanically, the relationship between miR-526b-3p and VEGFA was disclosed by qRT-PCR. VEGFA and STAT3 interaction was confirmed by ChIP and luciferase reporter assay. MiR-526b-3p targeted STAT3 to reduce VEGFA transcription. We designed rescue assays and presented that the negative effects of miR-526b-3p on cardiac dysfunction and HUVECs were rescued by VEGFA reintroduction in DOX-affected mice. Overall, miR-526b-3p accelerated doxorubicin-induced cardiotoxicity through modulating STAT3/VEGFA, highlighting that targeting miR-526b-3p as a potential method to protect against DOX-induced cardiac dysfunction.
阿霉素（DOX）是一种广谱化疗药物，在血液疾病和实体瘤治疗中已被证实具有心脏毒性副作用。然而，DOX 诱导血管稳态异常的机制在很大程度上仍难以捉摸。qRT-PCR 和免疫组织化学染色表明，DOX 处理的小鼠心脏中 miR-526b-3p 增加，CD31 和 CD34 减少。通过转染 miR-526b-3p 模拟物或抑制剂到人脐静脉内皮细胞（HUVECs）和 rAAV 在小鼠中的给药，检测了 miR-526b-3p 对心脏功能和心肌微血管密度的调节作用。通过 EdU、流式细胞术、管形成和 Transwell 测定检测 HUVECs 的增殖、凋亡、管形成和迁移。qRT-PCR 揭示了 miR-526b-3p 与 VEGFA 之间的关系。ChIP 和荧光素酶报告基因测定证实了 VEGFA 和 STAT3 之间的相互作用。miR-526b-3p 通过靶向 STAT3 减少 VEGFA 转录。我们设计了挽救实验，并提出在 DOX 作用的小鼠中通过 VEGFA 再导入来挽救 miR-526b-3p 对心脏功能障碍和 HUVECs 的负面影响。总的来说，miR-526b-3p 通过调节 STAT3/VEGFA 加速了阿霉素诱导的心脏毒性，这表明靶向 miR-526b-3p 可能是一种预防 DOX 诱导的心脏功能障碍的潜在方法。
