A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus

• Published in: Nature communications Vol. 11; no. 1; pp. 6135 - 16
• Main Authors: Simion, Viorel, Zhou, Haoyang, Haemmig, Stefan, Pierce, Jacob B., Mendes, Shanelle, Tesmenitsky, Yevgenia, Pérez-Cremades, Daniel, Lee, James F., Chen, Alex F., Ronda, Nicoletta, Papotti, Bianca, Marto, Jarrod A., Feinberg, Mark W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/89; 38; 38/71; 38/90; 42; 59; 631/80/304; 631/80/82; 692/4019; 692/4019/592; Animals; Aorta; Apoptosis; Arteriosclerosis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - physiopathology; Caspase-9; Cell Nucleus - genetics; Cell Nucleus - metabolism; ELAV-Like Protein 1 - genetics; ELAV-Like Protein 1 - metabolism; Humanities and Social Sciences; Humans; HuR protein; Inflammation; Lesions; Lipids; Macrophages; Macrophages - cytology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Non-coding RNA; p53 Protein; Protein Transport; Regulators; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA-binding protein; Science; Science (multidisciplinary); Species Specificity; Tethering; Vascular diseases
• ISSN: 2041-1723; 2041-1723
• 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. Long non coding RNA molecules have been implicated in the immunopathology of a range of inflammatory pathologies. Here the authors show lncRNA MAARS regulates apoptosis via interaction with HuR in the context of atherosclerosis.