MiR-320a通过靶向抑制VEGF信号通路介导阿霉素心脏损伤  

MiR-320a mediates doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway

作　　者：何梦颖 殷中伟 赵艳茹 李华萍 文铮 蒋建刚[1,2] HE Meng-ying;YIN Zhong-wei;ZHAO Yan-ru;LI Hua-ping;WEN Zheng;JIANG Jian-gang(Division of Cardiology,Department of Internal Medicine,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030;Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders,Wuhan 430030,China)

机构地区：[1]华中科技大学同济医学院附属同济医院心血管内科,武汉市430074 [2]心血管病遗传与分子机制湖北省重点实验室,武汉市430074

出　　处：《中国分子心脏病学杂志》2018年第5期2594-2599,共6页Molecular Cardiology of China

基　　金：国家自然科学基金(81600314);湖北省自然科学基金(2018CFB552)

摘　　要：目的探讨miR-320a在阿霉素心脏损伤中的作用与机制。方法在体实验中,我们在C57BL6小鼠上建立了阿霉素心脏损伤的动物模型。在造模之前应用重组腺相关病毒转导系统(rAAVs)来调控miR-320a在小鼠体内的表达,干预阿霉素后,通过Real-time PCR检测miR-320a的水平,通过血流动力学、心脏超声和形态学等方法检测各组小鼠心功能和心肌细胞面积。体外实验中,通过转染miR-320a mimics或inhibitor调控能内皮细胞miR-320a表达,检测内皮细胞增殖、凋亡、迁移和成管。结果阿霉素使心脏组织的miR-320a显著上调。高表达miR-320a加重了阿霉素引起的心功能恶化以及心肌细胞肥大。在体外实验中我们发现高表达miR-320a能抑制内皮细胞增殖,促进凋亡,使其迁移及成管能力下降,而采用miRNA inhibitor降低miR-320a表达则能减少阿霉素引起的损伤。同时我们证实VEGF-A是miR-320a的靶点。在体内腺相关病毒靶点回输实验中,在高表达miR-320a的基础上高表达VEGF-A减轻了miR-320a高表达造成的阿霉素对心脏心功能的损伤作用。结论 miR-320a通过调控内皮细胞功能介导了阿霉素的心脏损伤作用,抑制miR-320a具有缓解阿霉素心脏损伤的临床价值。Objective To explore the role of miR-320a in doxorubicin induced cardiotoxicity. Methods Firstly, animal models of doxorubicin induced cardiotoxicity were established in C57 BL/6 mice. Real-time PCR were used to detect miR-320a level. Secondly, recombinant adenoassociated virus(rAAV) in vivo and miR-320a mimics/inhibitors in vitro were used to further explore the roles of miR-320a in doxorubicin induced cardiotoxicity. Lastly, target prediction showed that VEGF-A was a potential target of miR-320a, which was verified by anti-Ago2 coimmunoprecipitation and Western blots. To verify the function of VEGF-A in doxorubicin induced impairment, VEGF-A was over-expressed by rAAV in mice. Results Significantly increased level of miR-320a was found by after doxorubicin treatment, which was relative specificity in heart and endothelial cells. Knockdown of miR-320a not only resulted in enhanced proliferation and inhibited apoptosis in cultured endothelial cells, but also attenuated cardiac abnormalities induced by doxorubicin. On the contrary, overexpression of miR-320a enhanced apoptosis in vitro, and aggravated subsequent cardiac dysfunction in mice, while knockdown miR-320a or re-expression of VEGF-A eliminated the destructive effects of miR-320 in doxorubicin induced cardiotoxicity. Conclusion MiR-320a mediates doxorubicin induced cardiotoxicity by targeting VEGF signal pathway and thus,inhibition of miR-320a may be applied to the treatment of cardiac dysfunction induced by anthracycline.

关 键 词：心脏损伤 阿霉素 miR-320a VEGF-A 

分 类 号：R730.5[医药卫生—肿瘤]