miR-320a mediates doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway.
miR-320a mediates doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway.
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miR-320a通过靶向VEGF信号通路介导阿霉素诱导的心脏毒性
DOI：
10.18632/aging.100876
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Wang DW
中科院分区：
文献类型：
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作者：
Yin Z;Zhao Y;Li H;Yan M;Zhou L;Chen C;Wang DW
背景血管稳态异常可能参与阿霉素的心脏毒性。方法蒽环类药物阿霉素可诱导小鼠心肌miR-320 a表达增加，心肌微血管密度降低，心功能受损。为了进一步探索miR-320 a在阿霉素诱导的心脏毒性中的作用，在小鼠中采用体外microRNA模拟物/抑制剂和体内rAAV施用。结果下调miR-320 a不仅能促进内皮细胞增殖，抑制内皮细胞凋亡，而且能减轻阿霉素诱导的心脏异常。相反，miR-320 a的过表达在体外增强了细胞凋亡，并加重了小鼠心脏中的血管异常和随后的心功能障碍。Western blot结果表明，VEGF-A是miR-320 a的潜在靶点，并通过抗Ago 2免疫共沉淀实验证实了这一点。与miR-320 a一样，针对VEGF-A的siRNA能增强阿霉素诱导的内皮细胞损伤。最后，阿霉素治疗小鼠中VEGF-A的重新表达减轻了miR-320 a对血管稳态和心脏功能的负面影响。结论miR-320 a在阿霉素的心脏毒性中起重要作用，可能通过维持心脏血管的稳态发挥作用，因此，抑制miR-320 a可用于治疗蒽环类药物所致的心功能不全。
Background Vascular homeostasis abnormalities may involve in doxorubicin induced cardiotoxicity. Methods Enhanced cardiac miR-320a expression, reduced cardiac microvessel density and impaired cardiac function were observed in mice treated by anthracycline doxorubicin. To further explore the role of miR-320a in doxorubicin induced cardiotoxicity, microRNA mimics/inhibitor in vitro and rAAV administration in vivo were employed in mice. Results 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 vessel abnormalities in heart and subsequent cardiac dysfunction in mice. Furthermore, Western blot assays showed that VEGF-A was a potential target of miR-320a, which was verified by anti-Ago2 co-immunoprecipitation. Moreover, as same as miR-320a, siRNA against VEGF-A reinforced doxorubicin induced endothelial cells injury. Finally, the negative effects of miR-320a on vascular homeostasis and cardiac function were alleviated by VEGF-A re-expression in doxorubicin treated mice. Conclusion Our observations demonstrate that miR-320a play important roles in doxorubicin induced cardiotoxicity via vessel homeostasis in heart and thus, inhibition of miR-320a may be applied to the treatment of cardiac dysfunction induced by anthracycline.