Xu Jinfeng, Zhang Qian, Wang Rong, Yang Jianbo
The Department of Second Neurology, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000, China.
The Department of Second Brain Disease, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000, China.
Biochem Biophys Rep. 2025 Jul 30;43:102173. doi: 10.1016/j.bbrep.2025.102173. eCollection 2025 Sep.
Atherosclerotic cardiovascular disease (ASCVD) is a major cause of death and disability worldwide. The pathological basis of these conditions is atherosclerosis (AS), which is associated with high mortality and significant morbidity rates. Long non-coding RNAs (lncRNAs) are crucial in various human diseases, including ASCVD; however, the specific mechanisms by which disease-associated lncRNAs are involved in ASCVD are not fully understood. In our study, we observed upregulated expression of metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) and DNA hypomethylation levels in ASCVD patients. To investigate the role of MALAT1 in ASCVD, we used oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages as a cellular model. Functional experiments demonstrated that the knockdown of MALAT1 reversed ox-LDL-mediated inhibition of cell viability, promotion of apoptosis, cholesterol metabolism imbalance, and inflammatory responses. Furthermore, inhibition of MALAT1 ameliorated the progression of AS in ApoE mice by suppressing cholesterol metabolism and inflammation. Mechanistically, DNA methyltransferase 1 (DNMT1)-mediated DNA methylation modification inhibited the expression of lncRNA MALAT1, which in turn inhibbited the activation of the nuclear factor-κB (NF-κB) signaling pathway. Additionally, rescue experiments indicated that increasing DNMT1 levels attenuated ox-LDL-induced malignant progression of ASCVD, and this reduction was reversed by elevating MALAT1 levels. Notably, when NF-κB was inhibited (BAY11-7082) alongside MALAT1 overexpression, the reversal effect was abolished. Taken together, our findings suggest that decreased DNA hypomethylation mediated by DNMT1 leads to increased MALAT1 expression, subsequently activating the NF-κB pathway in ASCVD.
动脉粥样硬化性心血管疾病（ASCVD）是全球范围内死亡和残疾的主要原因。这些病症的病理基础是动脉粥样硬化（AS），它与高死亡率和显著的发病率相关。长链非编码RNA（lncRNAs）在包括ASCVD在内的各种人类疾病中起着关键作用；然而，与疾病相关的lncRNAs参与ASCVD的具体机制尚未完全明确。在我们的研究中，我们观察到ASCVD患者中转移相关的肺腺癌转录本-1（MALAT1）表达上调以及DNA低甲基化水平。为了研究MALAT1在ASCVD中的作用，我们使用氧化型低密度脂蛋白（ox-LDL）处理的THP-1巨噬细胞作为细胞模型。功能实验表明，敲低MALAT1可逆转ox-LDL介导的细胞活力抑制、细胞凋亡促进、胆固醇代谢失衡和炎症反应。此外，抑制MALAT1通过抑制胆固醇代谢和炎症改善了ApoE小鼠的AS进展。机制上，DNA甲基转移酶1（DNMT1）介导的DNA甲基化修饰抑制了lncRNA MALAT1的表达，进而抑制了核因子-κB（NF-κB）信号通路的激活。此外，拯救实验表明，增加DNMT1水平可减弱ox-LDL诱导的ASCVD恶性进展，而这种降低可通过提高MALAT1水平来逆转。值得注意的是，当NF-κB被抑制（BAY11-7082）同时MALAT1过表达时，这种逆转作用被消除。综上所述，我们的研究结果表明，DNMT1介导的DNA低甲基化减少导致MALAT1表达增加，随后在ASCVD中激活NF-κB通路。
