# MDM2-HIF signaling in pathological ventricular remodeling

> **NIH NIH R56** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $597,257

## Abstract

Project Summary:
Multiple acquired and genetic conditions can lead to pathological left ventricular hypertrophy (LVH).
Importantly, it has been recognized for over 50 years that pathological LVH is associated with heart failure and
increased mortality in the human population. In addition, LVH is strongly associated with both heart failure with
preserved systolic function (HFpEF) and heart failure with reduced systolic function (HFrEF). At the tissue
level, the primary cause of LVH is cardiomyocyte hypertrophy and there are a multitude of intracellular
signaling pathways involved in hypertrophic cardiomyocyte growth. However, non-cardiomyocyte myocardial
cell populations also contribute to the pathological remodeling in LVH and the downstream sequelae of this
condition. For example, in many forms of human cardiomyopathy there are reductions in myocardial capillary
density which is thought to contribute to myocardial dysfunction in these diseases. Therefore, it is not only
critical to understand the primary causes of pathological cardiomyocyte growth but also how the myocardial
microenvironment responds to these changes. To uncover the mechanisms regulating LVH and pathological
remodeling in the mammalian heart, we utilized murine models that allow manipulation of the sarcomere
protein, cardiac myosin binding protein 3 (MYBPC3). We discovered that loss of MYBPC3 protein causes rapid
changes in cardiomyocyte growth through dysregulated cell cycle pathways causing cardiomyocyte
endoreplication (DNA replication without cell division). We then determined that the dysregulated
cardiomyocyte DNA synthesis in sarcomeric cardiomyopathy leads to replication stress induced DNA damage
in cardiomyocytes and activation of DNA damage response (DDR) pathways. We have now identified that the
DDR effector protein, murine double mutant 2 (MDM2), plays a crucial role in pathological left ventricular
remodeling in both genetic and acquired forms of left ventricular hypertrophy. We hypothesize that dynamic
changes in MDM2 and HIF signaling accelerate pathological hypertrophic remodeling by altering both the
myocardial microvasculature and cardiac metabolism. To test this hypothesis, we will pursue the following
aims: Aim 1: Define the role of MDM2 and the HIF switch in altering the myocardial microvasculature in genetic
forms of LVH. Aim 2: Determine if MDM2 and the HIF switch alters cardiomyocyte metabolism in genetic forms
of LVH. Aim 3: Define which components of cardiomyocyte MDM2-HIF signaling are regulating pathological LV
remodeling in acquired forms of LVH. At the conclusion of these innovative and high impact studies, we will
have defined a novel role for MDM2-HIF signaling during key periods of pathological left ventricular
hypertrophy secondary to both genetic and acquired causes. Through selective modulation of key components
of this pathway our goal is to disrupt key maladaptive myocardial remodeling responses and uncover novel
therapeutic opportunities fo...

## Key facts

- **NIH application ID:** 10705352
- **Project number:** 1R56HL160890-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jason Becker
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $597,257
- **Award type:** 1
- **Project period:** 2022-09-23 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705352

## Citation

> US National Institutes of Health, RePORTER application 10705352, MDM2-HIF signaling in pathological ventricular remodeling (1R56HL160890-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10705352. Licensed CC0.

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