Department of Emergency, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Neurology, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China.
J Cell Physiol. 2018 Oct;233(10):6996-7003. doi: 10.1002/jcp.26622. Epub 2018 May 8.
Atherosclerosis is a kind of chronic inflammation disease with lipid accumulation in in blood vessel linings. Increasing evidence has reported that microRNAs can exert crucial roles in atherosclerosis. In previous study, miR-181a has been implicated to be abnormally expressed in atherosclerosis mice, however its detailed function in atherosclerosis remains uninvestigated. Hence, in our current study, we focused on the biological role of miR-181a in atherosclerosis progression. Ox-LDL has been commonly identified as an important atherosclerosis regulator. We observed that ox-LDL induced THP-1 cell apoptosis dose-dependently and time- dependently. Meanwhile, 25 µg/ml ox-LDL can promote foam cell formation and increased miR-181a expression significantly. CD36 has been involved in atherosclerosis progression and it was found that overexpression of miR-181a inhibited its protein levels. Moreover, miR-181a mimics repressed foam cell formation, TC and TG levels induced by ox-LDL dramatically. In addition, miR-181a mimics were able to reverse THP-1 cell apoptosis, increased IL-6, IL-1β, and TNF-α protein expression triggered by 25 µg/ml ox-LDL. TLR4 has been linked to various inflammation-associated diseases. In our present study, TLR4 was indicated as miR-181a target and the binding correlation between them was validated by dual-luciferase reporter assay. In conclusion, these results improves the understanding of atherosclerosis modulated by miR-181a/TLR4 and can contribute to development of new approaches for atherosclerosis.
动脉粥样硬化是一种以血管内膜脂质积聚为特征的慢性炎症性疾病。越来越多的证据表明，microRNAs 在动脉粥样硬化中发挥着关键作用。在之前的研究中，miR-181a 在动脉粥样硬化小鼠中被发现表达异常，但它在动脉粥样硬化中的详细功能仍未被研究。因此，在我们目前的研究中，我们专注于 miR-181a 在动脉粥样硬化进展中的生物学作用。氧化低密度脂蛋白（ox-LDL）已被普遍认为是一种重要的动脉粥样硬化调节剂。我们观察到 ox-LDL 诱导 THP-1 细胞凋亡呈剂量依赖性和时间依赖性。同时，25μg/ml ox-LDL 可以促进泡沫细胞形成，并显著增加 miR-181a 的表达。CD36 参与动脉粥样硬化的进展，研究发现过表达 miR-181a 可抑制其蛋白水平。此外，miR-181a 模拟物可显著抑制 ox-LDL 诱导的泡沫细胞形成，降低 TC 和 TG 水平。此外，miR-181a 模拟物能够逆转由 25μg/ml ox-LDL 触发的 THP-1 细胞凋亡，增加 IL-6、IL-1β 和 TNF-α 蛋白表达。TLR4 与多种炎症相关疾病有关。在本研究中，TLR4 被确定为 miR-181a 的靶标，并通过双荧光素酶报告基因检测验证了它们之间的结合相关性。总之，这些结果提高了对 miR-181a/TLR4 调节动脉粥样硬化的理解，并为动脉粥样硬化的新治疗方法的发展做出贡献。
