# The pluripotency factor OCT4 plays an athero-protective role in endothelial cells

> **NIH NIH R56** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $402,500

## Abstract

ABSTRACT
 Atherosclerosis is a chronic disease of the arterial wall which contributes to >40% of all deaths in the USA.
Although previous studies provide clear evidence for the importance of endothelial cell (EC) activation and
phenotypic modulation during atherosclerosis, little is known about key regulatory mechanisms for EC plasticity
that influence lesion growth and/or stability. Recently, we found that the embryonic stem cell/iPS factor OCT4
that was believed to be silenced in somatic cells plays an athero-protective role in smooth muscle cells (SMC)
by regulating SMC phenotypic transitions. We then asked if OCT4 might also play a key role in regulating
plasticity of EC during atherosclerosis development. Our preliminary results using a novel EC-specific Oct4
knockout Apoe-/- mouse model demonstrated that loss of Oct4 in EC increases the total lipid burden within aortas
and occurrence of plaques within pulmonary arteries of Apoe-/- mice fed a long-term high-fat diet, indicating that
OCT4 plays a key functional role within EC. To further understand molecular mechanisms whereby EC-derived
OCT4 inhibits the accumulation of lipids we performed a single cell (sc)RNA-seq analysis on the aortic and lung
EC sorted from EC-Oct4 knockout and wild-type Apoe-/- mice fed a Western diet for five weeks. Differential gene
expression analyses identified 405 (aorta), and 250 (lung) significantly dysregulated genes in Oct4 knockout EC
as compared to wild type EC, including upregulation of genes involved into Endothelial-to-Mesenchymal
transition (Endo-MT), pro-inflammatory and adhesion molecules, and down-regulation of genes involved into
xenobiotic and heme metabolism. Also, using results from the in vivo OCT4 ChIP-seq, we found that one of the
genes significantly down-regulated in the Oct4 knockout lung and aortic EC, Abcg2, is a putative target of OCT4.
ABCG2 is an ATP-binding cassette transporter responsible for extruding toxic xenobiotics, including heme from
cells. Previous studies demonstrated that EC-derived ABCG2 plays a pivotal role in cardiac repair after
myocardial infarction and protective role against oxidative stress and neuroinflammatory response in mouse
brains by inhibiting NF-kB-signaling. However, there is no data about the potential protective role of ABCG2 in
EC during atherosclerosis development. Our overall hypothesis is that the pluripotency factor OCT4 plays a
critical athero-protective role in EC during the development of atherosclerosis through activation of the
gatekeeper protein ABCG2, an adaptive mechanism to decrease oxidative stress and protect EC from ROS-
induced activation and inflammatory response. Aim 1 will test the hypothesis that OCT4 plays an athero-
protective role by preventing EC from activation and phenotypic modification at the early and late stages of
atherosclerosis. Aim 2 will test the hypothesis that OCT4 attenuates EC-activation and EC inflammatory
response at least in part through up-regulating Abcg2 that pr...

## Key facts

- **NIH application ID:** 10266228
- **Project number:** 1R56HL148025-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Olga Cherepanova
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266228

## Citation

> US National Institutes of Health, RePORTER application 10266228, The pluripotency factor OCT4 plays an athero-protective role in endothelial cells (1R56HL148025-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10266228. Licensed CC0.

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