Rap1A accelerates homocysteine-induced ANA-1 cells inflammation via synergy of FoxO1 and DNMT3a.
Rap1A accelerates homocysteine-induced ANA-1 cells inflammation via synergy of FoxO1 and DNMT3a.
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DOI：
10.1016/j.cellsig.2023.110627
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发表时间：
2023-02
影响因子：
4.8
通讯作者：
Hui Wu;Zhen Li;Yali Yang;Lin Zhang;Yin Yuan;Yanjia Wang;Guizhong Li;Xiaoling Yang
中科院分区：
文献类型：
--
作者：
Hui Wu;Zhen Li;Yali Yang;Lin Zhang;Yin Yuan;Yanjia Wang;Guizhong Li;Xiaoling Yang
同型半胱氨酸(Hcy)水平的异常升高通过促进巨噬细胞炎症而加速动脉粥样硬化，但其确切机制尚不清楚。先前的研究表明，Rap1a参与了动脉粥样硬化的发生发展，但对Hcy诱导的巨噬细胞炎症的调节及其可能的机制知之甚少。在本研究中，我们证明了同型半胱氨酸上调了ANA-1细胞中RAP1A的表达，并抑制了促炎细胞因子IL-6和肿瘤坏死因子-α的水平。从机制上讲，DNMT3a介导的RAP1A启动子DNA低甲基化加速了Hcy诱导的ANA-1细胞炎症。此外，FoxO1通过直接与其启动子结合来转录激活Rap1a。更重要的是，Hcy可以增强FoxO1与DNMT3a的相互作用，协同促进Rap1A的表达，从而加速ANA-1细胞的炎症反应。这些数据表明，Rap1a在Hcy诱导的ANA-1细胞炎症中是一个新的和重要的调节因子。
Abnormal elevation of homocysteine (Hcy) level accelerates atherosclerosis through promote macrophage inflammation, while the precise mechanisms remain to be well elucidated. Previous study revealed that Rap1A is involved in the development of atherosclerosis, but little is known regarding the regulation of macrophage inflammation induced by Hcy and its potential mechanisms. In the present study, we demonstrated that Hcy upregulates Rap1A expression and knockdown of Rap1A inhibited pro-inflammatory cytokines IL-6 and TNF-α levels in ANA-1 cells. Mechanistically, DNMT3a-mediated DNA hypomethylation of Rap1A promoter accelerates Hcy-induced ANA-1 cells inflammation. Furthermore, FoxO1 transcriptionally activate Rap1A by direct binding to its promoter. More importantly, Hcy could enhance FoxO1 interaction with DNMT3a and synergistically promote the expression of Rap1A resulting in accelerate ANA-1 cells inflammation. These data indicate that Rap1A is a novel and important regulator in Hcy-induced ANA-1 cells inflammation.