# MerTK as a new target to understand and ameliorate HFpEF

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2021 · $41,389

## Abstract

Project Summary/Abstract
 Heart failure with preserved ejection fraction (HFpEF) is an epidemic and the incidence is continuing to
rise. Despite the prevalence of HFpEF, classical heart failure treatments and novel drug targets have failed to
elucidate an effective therapy. HFpEF is characterized by “damage from without” the myocardium with extra-
cardiac comorbidities such as obesity, hypertension and metabolic syndrome. A chronic state of systemic low-
grade inflammation induces reactive oxygen species (ROS) production in endothelial cells and nitrosative stress.
This culminates in impaired cardiomyocyte relaxation preventing proper filling of the left ventricle and reduced
cardiac reserve.
 The innate immune system is a driving force behind HFpEF. As a result of systemic inflammation,
monocyte migration into the sub-endothelium is promoted by upregulations in vascular cell adhesion molecule
(VCAM) and E-selectin on endothelial cells. Additionally, cardiac biopsies of HFpEF patients show elevations in
the pro-fibrotic cytokine transforming growth factor (TGF)-β. Along with observed increased cardiac fibrosis, this
suggests a role for the activation of macrophages (Mɸ), however, their exact function in HFpEF pathophysiology
is unknown.
 Clinically, elevations in the solubilized form of Mɸ anti-inflammatory receptor MerTK (solMER) have led
us to explore its function in HFpEF. MerTK plays an important role in maintaining tissue homeostasis through
phagocytosis of apoptotic cells (efferocytosis). However, MerTK also plays a role in cell survival, lipid uptake,
and inflammation resolution. MerTK has previously been implicated in cardiac repair after ischemic injury by
promoting phagocytosis of dying cardiomyocytes. Interestingly, in contrast to ischemic injury, our preliminary
data suggest that MerTK may be promoting HFpEF instead of acting in its usual cardioprotective role.
 Specifically, this proposal hypothesizes that Mɸ MerTK exacerbates the development or
persistence of HFpEF through the promotion of excessive MerTK-stimulated cardiac fibrosis triggered
by the combined HFpEF risk factors of high fat and nitrosative stress. This hypothesis will be tested using
mouse models of HFpEF in combination with MerTK knockout and inhibition. Mechanism-specific questions will
be supplemented with in vitro gene expression characterization. The proposed studies will identify a potential
new drug target for treatment and prevention of HFpEF, something desperately needed in clinic.

## Key facts

- **NIH application ID:** 10140035
- **Project number:** 1F31HL156408-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mallory Filipp
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $41,389
- **Award type:** 1
- **Project period:** 2021-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140035

## Citation

> US National Institutes of Health, RePORTER application 10140035, MerTK as a new target to understand and ameliorate HFpEF (1F31HL156408-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10140035. Licensed CC0.

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