Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis. Using RNA-seq profiling of the intima of lesions, here we identify a macrophage-specific lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). Aortic intima expression of MAARS increases by 270-fold with atherosclerotic progression and decreases with regression by 60%. MAARS knockdown reduces atherosclerotic lesion formation by 52% in LDLR^−/− mice, largely independent of effects on lipid profile and inflammation, but rather by decreasing macrophage apoptosis and increasing efferocytosis in the vessel wall. MAARS interacts with HuR/ELAVL1, an RNA-binding protein and important regulator of apoptosis. Overexpression and knockdown studies verified MAARS as a critical regulator of macrophage apoptosis and efferocytosis in vitro, in an HuR-dependent manner. Mechanistically, MAARS knockdown alters HuR cytosolic shuttling, regulating HuR targets such as p53, p27, Caspase-9, and BCL2. These findings establish a mechanism by which a macrophage-specific lncRNA interacting with HuR regulates apoptosis, with implications for a broad range of vascular disease states.

长链非编码 RNA (lncRNA) 是包括动脉粥样硬化在内的病理生理过程的新兴调节因子。使用病变内膜的 RNA-seq 分析，我们在这里鉴定了巨噬细胞特异性 lncRNA MAARS（巨噬细胞相关的动脉粥样硬化 lncRNA 序列）。MAARS的主动脉内膜表达随着动脉粥样硬化的进展增加了 270 倍，随着消退减少了 60%。MAARS敲低使 LDLR ^-/-小鼠的动脉粥样硬化病变形成减少了 52% ，这在很大程度上独立于对脂质谱和炎症的影响，而是通过减少巨噬细胞凋亡和增加血管壁中的细胞增多症。马尔斯与 HuR/ELAVL1 相互作用，HuR/ELAVL1 是一种 RNA 结合蛋白和细胞凋亡的重要调节因子。过表达和敲低研究证实MAARS是体外巨噬细胞凋亡和胞吐作用的关键调节因子，以 HuR 依赖性方式。从机制上讲，MAARS敲低会改变 HuR 细胞溶质穿梭，调节 HuR 靶标，例如 p53、p27、Caspase-9 和 BCL2。这些发现确立了巨噬细胞特异性 lncRNA 与 HuR 相互作用调节细胞凋亡的机制，这对广泛的血管疾病状态具有重要意义。