# Attenuation of atherosclerosis by regulation of VSMC  inflammatory gene mRNA stability

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $491,772

## Abstract

Our overarching hypothesis is that FXR1 activity may be a compensatory, anti-inflammatory
activity in VSMC. Vascular smooth muscle cells (VSMC) play a critical role in the etiology and
progression of many vascular diseases including atherosclerosis and restenosis. Reduction of
inflammatory gene expression in VSMC is a rational approach to limit the severity of these
diseases. Our laboratory has found that one anti-inflammatory interleukin, IL-19, can decrease
vascular inflammation by reduction in mRNA stability of inflammatory transcripts by reduction of
activity of HuR, an mRNA stability protein. HuR translocates from the nucleus to the cytoplasm
where it recognizes elements present almost exclusively in the 3'UTR of pro-inflammatory genes.
Proteins and pathways which limit HuR translocation may reduce inflammatory mRNA stability,
but are currently understudied. Using LC-MS/MS to identify HuR-interacting proteins under
different inflammatory conditions, we identified one protein termed Fragile X-related protein
(FXR1), which interacts with HuR in inflammatory, but not basal conditions, a novel finding.
Importantly, FXR1 mRNA expression is enhanced in muscle cells, and it's promoter contains
multiple cholesterol-response elements. Nothing has been reported on expression of FXR1 in
VSMC or function for FXR1 in vascular disease. We present preliminary data showing that FXR1
expression is increased in injured arteries and TNFα and oxLDL stimulated human VSMC, and
this expression is increased by IL-19. We show that siRNA knock down of FXR1 in VSMC
increases inflammatory mRNA stability, abundance of inflammatory proteins, and cholesterol
uptake, while over-expression of FXR1 decreases mRNA stability and inflammatory protein
abundance. Our hypothesis is that FXR1 expression is a compensatory, negative-regulatory
mechanism and functions by decreasing HuR activity and vascular inflammation by decreasing
the stability of pro-inflammatory transcripts by numerous mechanisms. The overall goal of this
application is twofold: 1- to identify the molecular mechanisms of FXR1 function in regulation of
HuR activity and mRNA stability of pro-inflammatory transcripts in VSMC, and; 2- determine if
modulation of FXR1 activity can reduce severity of atherosclerosis and vascular restenosis.

## Key facts

- **NIH application ID:** 9856496
- **Project number:** 5R01HL141108-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** MICHAEL V AUTIERI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $491,772
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856496

## Citation

> US National Institutes of Health, RePORTER application 9856496, Attenuation of atherosclerosis by regulation of VSMC  inflammatory gene mRNA stability (5R01HL141108-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9856496. Licensed CC0.

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