# Understanding the mechanism of AEBP1-mediated fibrosis post-cardiac injury in heart failure

> **NIH VA I01** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2024 · —

## Abstract

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality and is especially prevalent among
US veterans. Heart failure (HF) is one of the most common manifestations of CVD, and one of the main
underlying pathologic mechanisms is cardiac fibrosis. Fibrosis is a reparative mechanism that follows any type
of injury. In the heart, it leads to reduced tissue compliance, cardiomyocyte hypertrophy and apoptosis,
chamber dilation, and eventually HF. HF patients undergoing implantation of a left ventricular assist device or
heart transplantation present a unique opportunity as cardiac tissue becomes available at the time of the above
operations. Our studies in HF patients have identified adipocyte enhancer binding protein 1 (AEBP1) as a
major node associated with myofibroblast activation, abnormal extracellular matrix (ECM) homeostasis, and
impaired wound healing following cardiac injury. Our goal is to investigate the mechanisms by which the
aberrant expression of AEBP1 contributes to cardiac fibrosis and to exploit its inhibition as a potential
antifibrotic therapy. Our recent studies indicated the correlation of elevated AEBP1 with increased cardiac
fibrosis and myofibroblast activation. The overexpression of AEBP1 in primary fibroblasts led to the
upregulation of myofibroblast markers and ECM. Chromatin immunoprecipitation and sequencing identified
Runt-related transcription factor 1 (RUNX1) as a potential transcription factor regulating AEBP1 expression.
We will investigate the mechanisms by which RUNX1 regulates AEBP1 expression during cardiac
fibroblast activation and subsequent fibrosis development (Aim 1). We will perform manipulative
expression (overexpression or shRNA knockdown) of RUNX1 in conjunction with quantitative determination of
AEBP1 expression level. We will determine the cis regulatory element in the AEBP1 genomic region which
RUNX1 occupies during cardiac myofibroblast activation and fibrosis development following cardiac injury.
 Our previous studies have shown that the overexpression of AEBP1 in human primary fibroblasts is
associated with increased expression of RUNX1, mesenchyme homeobox (MEOX), and myocardin-related
transcription factor A (MRTF-A). The knockdown of AEBP1 in fibroblasts stimulated with transforming growth
factor beta (TGF-ß) led to a reduced expression of RUNX1, MEOX and MRTF-A. Our goal is to understand
the mechanistic involvement of RUNX1, MEOX, and MRTF-A in AEBP1-mediated cardiac fibrosis (Aim
2). By overexpressing RUNX1, MEOX, or MRTFA in primary fibroblasts we will identify the gene and protein
expression of myofibroblast markers and ECM in relation to AEBP1 expression and determine whether they
are downstream of AEBP1, suggesting a possible feedback loop mechanism. We will test if the knockdown of
RUNX1, MEOX, or MRTF-A in fibroblasts stimulated with TGF-ß will reduce myofibroblast activation and
fibrosis. In a mouse model of myocardial infarction (MI) and phenylephrine/angiotensin 2 (PE/...

## Key facts

- **NIH application ID:** 10703837
- **Project number:** 1I01BX006306-01
- **Recipient organization:** VA SALT LAKE CITY HEALTHCARE SYSTEM
- **Principal Investigator:** Stavros George Drakos
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10703837

## Citation

> US National Institutes of Health, RePORTER application 10703837, Understanding the mechanism of AEBP1-mediated fibrosis post-cardiac injury in heart failure (1I01BX006306-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10703837. Licensed CC0.

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