Long non-coding RNA NAV2-AS2 protects against atherosclerosis by regulating EndMT through sense-antisense hybrid formation with NAV2 mRNA.

Atherosclerosis is a major cause of cardiovascular diseases, leading to conditions such as ischemic heart disease and peripheral artery disease. Long non-coding RNAs (lncRNAs) have been shown to play a critical role in the pathogenesis of atherosclerosis. The present study uncovered lncRNA NAV2-AS2 as a newfound regulator of atherosclerosis, governing endothelial-to-mesenchymal transition (EndMT). In this study, a novel atherosclerosis-related lncRNA, NAV2-AS2, was identified through microarray analysis. We demonstrate that the expression of NAV2-AS2 was decreased in the blood serum of individuals suffering from atherosclerosis, the intima of ApoE atherosclerotic mouse model, as well as oxidized low-density lipoprotein (ox-LDL)-stimulated human aortic endothelial cells (HAECs). Compared with littermate controls, endothelial cell-specific NAV2-AS2 overexpression via adeno-associated virus (AAV) had a significant preventive and therapeutic effect on high-fat diet (HFD)-induced atherosclerosis in ApoE mice. We discovered that NAV2-AS2 is an inhibitor of EndMT. Mechanistically, NAV2-AS2 formed a sense-antisense RNA duplex with NAV2 mRNA and increased its stability, thereby increasing NAV2 mRNA level and subsequently the NAV2 protein level. This enhancement of NAV2 expression facilitated a stronger interaction between NAV2 and Snail, which is a transcription factor known to promote EndMT, resulting in the downregulation of Snail protein. Silencing NAV2 or overexpression of Snail counteracted the suppression on EndMT of NAV2-AS2. Collectively, our findings reveal a novel anti-atherosclerotic role for NAV2-AS2 and highlight its inhibitory effects on EndMT via the NAV2/Snail axis. NAV2-AS2 could act as a potential target for atherosclerosis-related diseases.