Wu Hui, Li Zhen, Yang Yali, Zhang Lin, Yuan Yin, Wang Yanjia, Li Guizhong, Yang Xiaoling
Heart Centre & Department of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan 75004, China.
School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan 750004, China.
Cell Signal. 2023 Jun;106:110627. doi: 10.1016/j.cellsig.2023.110627. Epub 2023 Feb 14.
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.
同型半胱氨酸（Hcy）水平异常升高通过促进巨噬细胞炎症反应加速动脉粥样硬化，但其确切机制仍有待充分阐明。先前的研究表明Rap1A参与动脉粥样硬化的发展，但关于Hcy诱导的巨噬细胞炎症反应的调控及其潜在机制知之甚少。在本研究中，我们证明Hcy上调Rap1A表达，敲低Rap1A可抑制ANA-1细胞中促炎细胞因子IL-6和TNF-α水平。机制上，DNMT3a介导的Rap1A启动子DNA低甲基化加速了Hcy诱导的ANA-1细胞炎症反应。此外，FoxO1通过直接结合其启动子转录激活Rap1A。更重要的是，Hcy可增强FoxO1与DNMT3a的相互作用并协同促进Rap1A的表达，从而加速ANA-1细胞炎症反应。这些数据表明Rap1A是Hcy诱导的ANA-1细胞炎症反应中的一种新型重要调节因子。
