# LncRNA MAARS, macrophage apoptosis, and atherosclerosis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $415,900

## Abstract

Atherosclerosis, a chronic arterial disease, involves multiple cellular processes including the accumulation of
intimal macrophages. Macrophage apoptosis is increased with progression of atherosclerosis, leading to
increased cell death and accumulation of cellular debris. This in turn may abrogate macrophage efferocytosis,
an important event for clearance of apoptotic or necrotic cells. Therefore, improving the efficiency of
macrophages in the clearance of intra-lesional cellular debris may provide a novel therapeutic approach to limit
atherosclerotic progression.
 Long non-coding RNAs (lncRNAs) have garnered widespread attention as emerging regulators of
diverse biological processes relevant to atherosclerosis. However, the identity and roles of specific lncRNAs
within atherosclerotic lesions are not well defined. Using RNA-Seq profiling to identify lncRNAs derived
specifically from the aortic intima of LDLR-/- mice during lesion progression and regression phases, we identify
the lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). MAARS was the highest
expressed lncRNA with a 300-fold increase after lesion progression and decreased by 70% with regression.
MAARS is a polyadenylated, macrophage- and nuclear-specific, lncRNA. Kinetic studies showed that MAARS
expression is markedly induced in macrophages differentiated from bone marrow, PBMCs, or splenocytes.
Our preliminary data demonstrate that systemic delivery of inhibitors to MAARS strongly reduced lesion size,
independent of effects on circulating lipid profile, but rather by decreased macrophage apoptosis and
increased efferocytosis in the vessel wall. Deficiency of MAARS reduced macrophage apoptosis induced by
different stimuli and increased macrophage efferocytosis in vitro. Mechanistically, lncRNA pulldown assays in
combination with LC-MS/MS analysis showed that MAARS interacts with HuR, an RNA-binding protein and
important regulator of apoptosis. Preliminary studies show that HuR silencing increases macrophage apoptosis
and that the MAARS-mediated effects on macrophage apoptosis may be HuR dependent. In addition, MAARS
knockdown altered HuR nuclear-cytoplasmic trafficking, and regulated important apoptotic genes. These
observations provide the foundation for the central hypothesis that MAARS deficiency, via regulatory effects on
HuR and specific macrophage apoptotic signaling pathways, reduces macrophage apoptosis, improves cellular
efferocytosis, and suppresses atherosclerosis. To address this further, in Aim1 we examine the role of MAARS
in regulating HuR-mediated macrophage apoptosis and efferocytosis; in Aim2, we assess how alterations of
MAARS expression affects short- and long-term atherosclerosis in vivo; and in Aim3, we examine the role of
the MAARS-HuR signaling axis in human cells and atherosclerotic lesions. Our studies will address a major
gap in our understanding of lncRNAs in atherosclerosis and inform how MAARS-mediated control of
macrophage apoptosis and...

## Key facts

- **NIH application ID:** 10413149
- **Project number:** 5R01HL153356-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MARK W FEINBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $415,900
- **Award type:** 5
- **Project period:** 2020-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413149

## Citation

> US National Institutes of Health, RePORTER application 10413149, LncRNA MAARS, macrophage apoptosis, and atherosclerosis (5R01HL153356-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10413149. Licensed CC0.

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