Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Nat Commun. 2020 Dec 1;11(1):6135. doi: 10.1038/s41467-020-19664-2.
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。我们使用病变内膜的 RNA-seq 分析，在此鉴定出一种巨噬细胞特异性 lncRNA MAARS（巨噬细胞相关动脉粥样硬化 lncRNA 序列）。MAARS 在动脉粥样硬化进展过程中使主动脉内膜的表达增加了 270 倍，而在消退时则降低了 60%。MAARS 敲低使 LDLR 小鼠的动脉粥样硬化病变形成减少了 52%，这主要不是通过影响脂质谱和炎症，而是通过减少巨噬细胞凋亡和增加血管壁中的噬作用。MAARS 与 HuR/ELAVL1 相互作用，HuR/ELAVL1 是一种 RNA 结合蛋白，是细胞凋亡的重要调节剂。过表达和敲低研究证实 MAARS 是体外巨噬细胞凋亡和噬作用的关键调节因子，其方式依赖于 HuR。从机制上讲，MAARS 敲低改变了 HuR 的细胞质易位，调节 HuR 的靶标，如 p53、p27、Caspase-9 和 BCL2。这些发现确立了一种机制，即一种与 HuR 相互作用的巨噬细胞特异性 lncRNA 调节细胞凋亡，这对广泛的血管疾病状态具有重要意义。
