Abstract
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.