# The role of shear induced endothelial ZBTB46 in atherosclerosis

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $390,000

## Abstract

Project Summary
Atherosclerosis is a significant cause of morbidity and mortality in the world, contributing to diseases such as
coronary artery disease, peripheral arterial disease, and stroke. It is known that atherosclerosis has a focal
propensity to areas of disturbed flow (d-flow) while areas of steady laminar flow (s-flow) are relatively protected.
Endothelial cell (EC) activation by d-flow is an early step in atherosclerosis, and it is known that ECs exposed to
d-flow show higher levels of inflammation, proliferation, apoptosis, and senescence. We have recently shown
that ZBTB46 is a flow regulated transcription factor in ECs, is down-regulated by d-flow, and that its
overexpression in ECs inhibits proliferation. While the role of ZBTB46 in atherosclerosis is not known, our
preliminary studies suggest that ZBTB46 regulates a number of genes in ECs potentially involved in
atherosclerosis, including P21 and SFRP2. We propose to test the overall hypothesis that decreased ZBTB46
expression in ECs in response to d-flow leads to downstream changes in EC gene expression including
decreased P21 and SFRP2 gene expression, promoting EC activation, apoptosis, and senescence, and
consequently a focal predisposition to atherosclerosis. We address three specific aims for this project: 1)
Determine the downstream targets of ZBTB46 involved in flow regulated EC proliferation. First by combining loss
of function and gain of function methods and various flow conditions, we will determine if P21 and/or SFRP2 are
responsible for the inhibitory effect of ZBTB46 on EC proliferation seen under s-flow. We will also test if P21 and
SFRP2 are direct or indirect targets of ZBTB46. Finally, to identify other potential targets of ZBTB46 as a
transcription factor, we will use ChIP-seq in ECs expressing ZBTB46, and use the data to test the role of other
potential downstream targets of ZBTB46 that could be involved in atherosclerosis in the future. 2) Determine the
role of flow regulated ZBTB46 on EC apoptosis, senescence, and inflammation. We will test if EC-ZBTB46
expression affects these aspects of EC function which are seen in atheroprone areas exposed to d-flow, by using
siRNA and adenovirus mediated overexpression of ZBTB46 under s-flow and d-flow conditions in conjunction
with relevant stimuli such as hydrogen peroxide and TNFa. 3) Determine the effect of EC-ZBTB46 on
atherosclerosis in vivo. As ZBTB46 is also expressed in classical dendritic cells which are known to affect
atherosclerosis, our team has developed hyperlipidemic EC-targeted ZBTB46-KO mice. Using these mice in
experimental models of atherosclerosis, we will determine if loss of ZBTB46 specifically in EC contributes to the
flow mediated susceptibility to atherosclerosis by promoting EC apoptosis, senescence, and/or inflammation.
Successful completion of our aims will potentially find a novel regulator of EC functions contributing to
atherosclerosis and may identify novel potential therapeutic targets...

## Key facts

- **NIH application ID:** 10171897
- **Project number:** 5R01HL150005-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Amir Rezvan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171897

## Citation

> US National Institutes of Health, RePORTER application 10171897, The role of shear induced endothelial ZBTB46 in atherosclerosis (5R01HL150005-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10171897. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*