# LncRNA SNHG12, vascular senescence, and atherosclerosis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $641,485

## Abstract

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
Small Nucleolar Host Gene-12 (SNHG12). SNHG12 is highly enriched in the vascular endothelium across
mice, pigs, and humans and is significantly reduced with atherosclerotic lesion progression, but increased with
regression. Our preliminary studies show that gapmeR-mediated silencing of SNHG12 potently accelerated
atherosclerotic lesion formation by over 2-fold in LDLR-/- mice. Remarkably, the increased lesional effects were
not driven by lipid-lowering or by inflammatory recruitment of lesional leukocytes, but rather by increased DNA
damage (γH2AX) and senescence (p16, p21, p27) in the vascular endothelium. Accumulating studies
demonstrate that vascular senescence induced by the DNA damage response (DDR) may adversely contribute
to chronic inflammation in atherosclerotic lesions. However, the mechanisms linking senescence and
atherosclerotic lesion formation remain poorly understood.
 LncRNAs play important regulatory roles by interacting with RNA, chromatin modifiers, or protein-
coding genes. Mechanistically, using a modified RNA IP (RIP)-mass spectrometry pulldown assay, we identify
that SNHG12 interacts with the DNA-dependent protein kinase (DNA-PK) to control the DNA-damage
response. Preliminary studies show SNHG12 deficiency in ECs significantly increased DNA damage, markers
of senescence, and EC permeability to LDL. Moreover, we demonstrate that the NAD+ precursor nicotinamide
riboside (NR), that suppresses endothelial senescence, may function in an SNHG12-dependent manner.
These observations provide the foundation for the central hypothesis that endothelial SNHG12 deficiency, via
regulatory effects on DNA-PK and the DNA damage response, promotes vascular senescence, senescence-
associated inflammation, and atherosclerosis. To elucidate this further, three aims are proposed. In Aim1, we
will delineate the molecular basis for SNHG12's ability to regulate DNA-PK-mediated DNA damage response
and vascular senescence in ECs. In Aim2, we will determine the effect of altering lncRNA SNHG12 expression
in an EC-specific manner on the DNA damage response and atherosclerotic progression and regression. In
Aim3, we will explore the molecular mechanisms by which stimuli repress and NR rescues SNHG12
expression in ECs, and we will determine whether the anti-senescent effects of NR are SNHG12-dependent.
This multi-disciplinary team in the fields of non-coding RNA biology, molecular imaging, nanomedicine,
bioinformatics, and atherosclerosis research will establish an unprecedented molecular view of this lncRNA in
lesions that can in...

## Key facts

- **NIH application ID:** 9973625
- **Project number:** 1R01HL148355-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MARK W FEINBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $641,485
- **Award type:** 1
- **Project period:** 2020-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973625

## Citation

> US National Institutes of Health, RePORTER application 9973625, LncRNA SNHG12, vascular senescence, and atherosclerosis (1R01HL148355-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973625. Licensed CC0.

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