# HEG1 in endothelial function and atherosclerosis

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $677,985

## Abstract

SUMMARY
Atherosclerosis is a chronic inflammatory disease that underlies heart attacks and stroke. The disease
preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), in part by altering expression of
flow-sensitive genes. While looking for flow-sensitive long non-coding RNAs, we identified the flow-sensitive
heart of glass (HEG1) gene as a potential target. Previous studies using HEG1 knockouts in zebra fish and mice
have demonstrated its critical role in cardiovascular development and vascular integrity, but its role and
mechanisms of action in vascular biology and atherosclerosis are far from clear. Recently, we generated exciting
preliminary data, including a single-cell RNAseq study using the mouse partial carotid ligation (PCL) model,
demonstrating that HEG1 expression is increased by stable flow (s-flow) and decreased under disturbed flow (d-
flow) conditions. HEG1 knockdown in human aortic endothelial cells (HAECs) induces inflammation, barrier
dysfunction, and endothelial-mesenchymal transition (EndMT), key pro-atherogenic processes. HEG1 has a long
N-terminal extracellular structure containing two highly glycosylated (Gly) domains (potential flow sensing
domain), three EGF-like (EGFL) domains containing highly conserved Cys clusters (potential redox-sensitive,
flow-sensing domain),a transmembrane (TM) domain, and the cytosolic C-terminal (C-term signal transduction)
domain. Our preliminary results show that HEG1 1) can be pulled with a HEG1 antibody or sheared to induce
Ca++ flux, and 2) is redox-sensitive in a Poldip2-dependent manner. Based on these exciting data, we
hypothesize that HEG1 protein is a redox-sensitive mechanosensor, mediating the atheroprotective effects of
stable flow, while HEG1 loss and malfunction by d-flow induces endothelial dysfunction leading to
atherosclerosis. We will test this hypothesis in three aims: Aim 1 will determine the role of HEG1 in flow-
dependent EC function (inflammation, EndMT, and permeability) using siRNA-mediated knockdown or
overexpression of HEG1 (using AAV-HEG1 expressing WT or 3 truncation mutants ΔGly, ΔEGFL or ΔTM+C-
term) in HAECs and immortalized mouse aortic ECs (iMAECs). EC-targeted HEG1-null mice (HEG1-EC-/-) will
be used without or with the AAV-HEG1 constructs for in vivo validation of EC function. Aim 2 will test if HEG1 is
a redox-sensitive mechanosensor by focusing on immediate changes (seconds) in intracellular calcium, acute
activation (seconds-minutes) of signaling proteins, and slow (>hours) cell changes in response to shear stress
or tensional force using magnetic beads coated with HEG1 mAb. For these studies, HAECs and iMAECs treated
with siHEG1 or the same AAV9-HEG1 constructs described in Aim 1 will be used. Aim 3 will determine the role
of HEG1 in atherosclerosis using HEG1-EC-/- mice injected with AAV-PCSK9. We will further test if transduction
with the AAV-HEG1 constructs can prevent atherosclerosis in HEG1-EC-/- mice. These studies will ...

## Key facts

- **NIH application ID:** 10272942
- **Project number:** 1R01HL158571-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Hanjoong Jo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $677,985
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10272942

## Citation

> US National Institutes of Health, RePORTER application 10272942, HEG1 in endothelial function and atherosclerosis (1R01HL158571-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10272942. Licensed CC0.

---

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