# ApoE receptor-2 in vascular disease progression and regression

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $702,327

## Abstract

The apoE receptor-2 (apoER2) encoding gene LRP8 is a major gene locus for premature atherosclerosis and
acute myocardial infarction. One apoER2 variant with the R952Q mutation (allele frequency 0.29) is associated
with a 2-4 fold increase risk of acute myocardial infarction. The relationship between LRP8 polymorphism and
cardiovascular disease risk is independent of plasma cholesterol levels, but the etiology associating apoER2
dysfunction with cardiovascular disease is unknown. The premise of this application is that apoER2 dysfunctions
impair smooth muscle and dendritic cell functions to adversely influence atherosclerosis progression and
regression. We have shown previously that apoER2 deficiency in hyperlipidemic Ldlr-/- mice accelerates
atherosclerotic lesion necrosis. ApoER2 deficiency also promotes formation of cell-poor but fibrotic-rich
neointima after endothelial denudation, suggestive of excessive senescence-associated secretory smooth
muscle cells. Additional in vitro data revealed that apoER2 interacts with the catalytic subunit of protein
phosphatase 2 (PP2A-C) in smooth muscle cells, and its absence impairs PP2A-C functions during metaphase-
anaphase transition, thereby causing cell cycle arrest, mitotic slippage, and premature cell senescence.
Additional preliminary studies also found apoER2 expression in CD11c+ dendritic cells and its deficiency leads
to persistent phosphorylation of the focal adhesion protein VASP and the impairment of migration and
efferocytosis. One goal of this project is to establish a mechanistic framework of how the cell surface receptor
apoER2 modulates these intracellular events in smooth muscle cells and dendritic cells. Another goal is to test
the hypothesis that apoER2 dysfunction in CD11c+ dendritic cells impedes lesion regression and works
synergistically with apoER2-deficient smooth muscle cells to accelerate lesion necrosis. Mechanistic studies
proposed in Aim 1 will interrogate whether cell surface receptor binding/recycling and signaling is sufficient or if
generation of an apoER2 intracellular cytoplasmic domain (ICD) peptide is required for efficient smooth muscle
cell cytokinesis and dendritic cell efferocytosis and migration. Aim 2 will compare the influence of apoER2
cytoplasmic splice variants and how the R952Q mutation impact on apoER2 protection against fibrotic neointimal
formation after endothelial denudation and advanced atherosclerotic lesion development in hyperlipidemic
Ldlr-/- mice. Aim 3 will use tissue-specific Lrp8 knockout mice as well as bone marrow transplant approach to
test the hypothesis that apoER2 dysfunction in CD11c+ dendritic cells reduces the capacity for atherosclerosis
lesion regression and act synergistically with smooth muscle apoER2 deficiency to accelerate atherosclerotic
lesion necrosis. These studies will offer novel mechanisms depicting how the cell surface receptor apoER2
modulates intracellular events associated with cell division and motility to impact c...

## Key facts

- **NIH application ID:** 9889159
- **Project number:** 5R01HL147403-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** David Yiu-Kwan Hui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $702,327
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889159

## Citation

> US National Institutes of Health, RePORTER application 9889159, ApoE receptor-2 in vascular disease progression and regression (5R01HL147403-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9889159. Licensed CC0.

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