ABSTRACT

Increasing evidences have confirmed that long non-coding RNA LOXL1-AS1 functions in multiple human diseases. Here, we aim to explore the function and mechanism of LOXL1-AS1 in modulating oxidized low-density lipoprotein (ox-LDL)-induced angiogenesis of endothelial cells (ECs). Presently, we found that LOXL1-AS1 and KLF6 were upregulated in ECs treated by Ox-LDL in a dose- and time-dependent manner while miR-590-5p was downregulated. Overexpression of LOXL1-AS1 aggravated Ox-LDL mediated ECs proliferation and migration, and promoted angiogenesis both in vitro and in vivo. On the contrary, enhancing miR-590-5p or inhibiting LOXL1-AS1 level led to suppressive effects on the proliferation, migration and angiogenesis of ECs. Moreover, LOXL1-AS1 upregulation promoted the expression of vascular endothelial growth factor (VEGF), MMPs (including MMP2, MMP9 and MMP14) and also activated VEGF/VEGFR2/PI3K/Akt/eNOS pathway. Mechanistically, LOXL1-AS1 works as a competitive endogenous RNA (ceRNA) by sponging miR-590-5p, which targeted at the 3ʹ-untranslated region (3ʹUTR) of KLF6. Additionally, the proliferation, migration and angiogenesis of ECs were elevated following KLF6 upregulation. By detecting the expression of LOXL1-AS1 and miR-590-5p in the serum of healthy donors and atherosclerosis patients, it was found that LOXL1-AS1 was upregulated in atherosclerosis patients (compared with healthy donors) and had a negative relationship with miR-590-5p. Taken together, LOXL1-AS1 promoted Ox-LDL induced angiogenesis via regulating miR-590-5p-modulated KLF6/VEGF signaling pathway. The LOXL1-AS1-miR-590-5p axis exerts a novel role in the progression of atherosclerosis.

 抽象的

越来越多的证据证实长链非编码RNA LOXL1-AS1在多种人类疾病中发挥作用。在这里，我们的目的是探讨LOXL1-AS1在调节氧化低密度脂蛋白（ox-LDL）诱导的内皮细胞（EC）血管生成中的功能和机制。目前，我们发现 Ox-LDL 处理的 EC 中 LOXL1-AS1 和 KLF6 以剂量和时间依赖性方式上调，而 miR-590-5p 下调。 LOXL1-AS1的过度表达加剧了Ox-LDL介导的EC增殖和迁移，并促进体外和体内血管生成。相反，增强miR-590-5p或抑制LOXL1-AS1水平会对ECs的增殖、迁移和血管生成产生抑制作用。此外，LOXL1-AS1上调促进血管内皮生长因子（VEGF）、MMP（包括MMP2、MMP9和MMP14）的表达，并激活VEGF/VEGFR2/PI3K/Akt/eNOS通路。从机制上讲，LOXL1-AS1 通过海绵 miR-590-5p 充当竞争性内源 RNA (ceRNA)，miR-590-5p 靶向 KLF6 的 3ʹ 非翻译区 (3ʹUTR)。此外，KLF6 上调后 EC 的增殖、迁移和血管生成均有所提高。通过检测健康供者和动脉粥样硬化患者血清中 LOXL1-AS1 和 miR-590-5p 的表达，发现 LOXL1-AS1 在动脉粥样硬化患者中表达上调（与健康供者相比），且与 miR-590-5p 呈负相关。 590-5p。综上所述，LOXL1-AS1 通过调节 miR-590-5p 调节的 KLF6/VEGF 信号通路促进 Ox-LDL 诱导的血管生成。 LOXL1-AS1-miR-590-5p 轴在动脉粥样硬化的进展中发挥着新的作用。