# miRNA-mediated reduction of VSMC foam cell formation

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $535,716

## Abstract

The transformation of vascular smooth muscle cells (VSMC) into foam cells leading to increased plaque
size and decreased stability is a key, yet understudied step in atherogenesis. Our work in the previous
funding cycle (HL117724) demonstrated that Interleukin-19 (IL-19), a novel, anti-inflammatory cytokine,
attenuates atherosclerosis by multiple anti-inflammatory effects on VSMC as well as by increasing lipid
uptake and efflux in macrophage. In published and preliminary studies described here, we show that IL-19
reduces lipid accumulation in VSMC, an atheroprotective event, but without modifying expression of lipid
receptors or transporters. IL-19 induces expression of miR133a, a muscle-specific miRNA previously
ascribed to regulate VSMC phenotype. Although unrecognized and unreported, we have identified that
miR133a can target and reduce expression of Low Density Lipoprotein Receptor Adaptor Protein 1,
(LDLRAP1), an adaptor protein which functions to internalize the LDL receptor. Patients with mutations in
LDLRAP1 have LDL receptor malfunction leading to hyperlipidemia and Autosomal Recessive
Hypercholesterolemia (ARH) disorder. Nothing at all is known about a role for miR133a in regulation of
lipid uptake and development of atherosclerosis. Similarly, nothing at all has been published about
LDLRAP1 expression, function, and participation in VSMC foam cell formation. We have reported that that
both miR133a and LDLRAP1 regulate oxLDL uptake in VSMC. LDLRAP1 is induced in VSMC by oxLDL, is
not detectible in normal medial VSMC, but is expressed in plaque and neointimal VSMC of injured arteries.
IL-19 can reduce LDLRAP1 expression and oxLDL uptake in VSMC. Both miR133a and LDLRAP1regulate
VSMC proliferation, previously unrecognized functions for these molecules. Preliminary studies indicate
that the LDLRAP1+/- mouse has increased atherosclerosis, but reduced restenosis. In this competitive
renewal application, we hypothesize that LDLRAP1 can be selectively reduced in VSMC because miR133a
is muscle specific, and that reduction of lipid uptake by VSMC is atheroprotective and could also attenuate
vascular proliferative syndromes. The overall goals of this application are to determine causative roles for
miR133a and LDLRAP1 in VSMC lipid uptake, proliferation, atherogenesis, cholesterol-induced phenotype
modulation, and vascular restenosis.

## Key facts

- **NIH application ID:** 10150061
- **Project number:** 5R01HL117724-07
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** MICHAEL V AUTIERI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $535,716
- **Award type:** 5
- **Project period:** 2013-07-23 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150061

## Citation

> US National Institutes of Health, RePORTER application 10150061, miRNA-mediated reduction of VSMC foam cell formation (5R01HL117724-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10150061. Licensed CC0.

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