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

Viorel Simion, Haoyang Zhou, Stefan Haemmig, Jacob B. Pierce, Shanelle Mendes, Yevgenia Tesmenitsky, Daniel Pérez-Cremades, James F. Lee, Alex F. Chen, Nicoletta Ronda, Bianca Papotti, Jarrod A. Marto and Mark W. Feinberg ()
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Viorel Simion: Harvard Medical School
Haoyang Zhou: Harvard Medical School
Stefan Haemmig: Harvard Medical School
Jacob B. Pierce: Harvard Medical School
Shanelle Mendes: Harvard Medical School
Yevgenia Tesmenitsky: Harvard Medical School
Daniel Pérez-Cremades: Harvard Medical School
James F. Lee: Dana-Farber Cancer Institute
Alex F. Chen: The Third Xiangya Hospital of Central South University
Nicoletta Ronda: University of Parma
Bianca Papotti: University of Parma
Jarrod A. Marto: Dana-Farber Cancer Institute
Mark W. Feinberg: Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19664-2

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