# Friend of GATA 2 (FOG2) S657G regulates ß1-adrenergic receptor and cardiac work to promote Coronary Microvascular Disease

> **NIH NIH R03** · UNIVERSITY OF PENNSYLVANIA · 2024 · $121,875

## Abstract

SUMMARY
Coronary Microvascular Disease (CMVD) accounts for 30-50% of ischemic heart disease and leads to angina,
myocardial infarction, heart failure with preserved ejection fraction, and cardiovascular death. It represents a
mismatch between blood supply, which can be affected by structural or functional abnormalities in the coronary
microvasculature, and cardiomyocyte demand for oxygen, which is largely driven by cardiac work and depends
on heart rate, blood pressure, and cardiomyocyte contractility. Despite its significant clinical burden, little is
known about the pathogenesis of CMVD, and there are no targeted therapies. In prior work, we identified a
variant in the Friend of GATA 2 (FOG2) coding sequence, FOG2S657G, which is associated with CMVD. In
preliminary studies using novel mouse and human induced pluripotent stem cell models of FOG2S657G, we
show that FOG2S657G increases expression of β1-adrenergic receptor. Our central hypothesis is that this
increased expression drives increased cardiac work, including heart rate and cardiomyocyte contractility, to
promote supply-demand mismatch and CMVD. Our objectives in this proposal are to obtain multiscale
preliminary transcriptional regulation and functional data to support an R01 application focused on
understanding the mechanism by which FOG2S657G may promote CMVD. Aim 1 is based on our preliminary
data which shows that MEF2 is the top transcription factor family mediating cardiac gene expression changes
due to FOG2S657G in vivo. We will determine the mechanism by which FOG2S657G increases ADR1B
expression. We will use transfection experiments, luciferase assays, and co-immunoprecipitation to define the
interactions between FOG2S657G and two key cardiac transcription factors, MEF2C and GATA4. In Aim 2, we
will establish the effects of FOG2S657G in regulating cardiac work, with a focus on heart rate and contractility,
and coronary blood flow. First, we will use the IonOptix contractility system (Westwood, MA) to measure
contractility in FOG2S657G iPSCs differentiated to cardiomyocytes relative to isogenic controls. We will measure
contractility in vivo using invasive pressure-volume loop measurements. Then, we will use implantable
telemetry to measure heart rate and blood pressure and echocardiography to assess cardiac morphology and
function in male and female mice with FOG2S657G. Finally, we will use novel SPECT imaging to measure
myocardial blood flow in cohorts of mice with and without FOG2S657G. The experiments outlined in this proposal
will help elucidate the relationship between FOG2S657G, increased β1-adrenergic receptor, and cardiac work.
This work is important because it will (1) give insight into mechanisms by which a human variant causes
CMVD, (2) help establish the role of adrenergic receptor signaling in CMVD and (3) give new insights into
disease pathogenesis and potentially driving future therapies.

## Key facts

- **NIH application ID:** 10950661
- **Project number:** 1R03HL174882-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Marie A Guerraty
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $121,875
- **Award type:** 1
- **Project period:** 2024-07-19 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10950661

## Citation

> US National Institutes of Health, RePORTER application 10950661, Friend of GATA 2 (FOG2) S657G regulates ß1-adrenergic receptor and cardiac work to promote Coronary Microvascular Disease (1R03HL174882-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10950661. Licensed CC0.

---

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