# Ectonucleotidases in ischemic heart disease

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $514,476

## Abstract

More than 1 million people in the United States suffer a myocardial infarction (MI) each year. Myocardial
infarction (MI) evokes an intense inflammatory response. Paracrine and autocrine released extracellular ATP
(eATP), signaling through purinergic P2 receptors (P2X and P2Y), is a potent modulator of macrophage and
fibroblast function. Extracellular ATP is hydrolyzed by the transmembrane protein Ectonucleoside triphosphate
diphosphohydrolase 1 (CD39) to yield adenosine monophosphate (AMP), thereby halting pro-inflammatory
ATP-mediated signaling. This goal of the project is to define the role of the macrophage and fibroblast-
expressed CD39 on post-MI cardiac repair. To accomplish this goal we propose the following: Aim 1: To
determine whether CD39 up-regulation is a protective mechanism that constrains autocrine ATP-driven
inflammation, preventing exaggerated macrophage responses, and protecting from adverse post-MI fibrosis we
will: 1) determine how CD39 activity impacts TLR-4-dependent and IL-4-dependent macrophage functions in
vitro, 2) determine the impact of CD39 activity on the in vivo macrophage phenotypic transition from
inflammatory to profibrotic functions during post-MI repair, and 3) Determine the role of macrophage CD39 on
post-MI repair fibrosis in vivo. Aim 2: To dissect the purinergic pathways involved in CD39-mediated restraint of
TGF-β1 activation of cardiac fibroblasts and determine the role of CD39 upregulation in modulating fibroblast
function and regulating cardiac repair following MI we will 1) determine the downstream targets through which
CD39 attenuates TGF-β1-mediated cardiac fibroblast inflammatory and fibrotic responses, 2) determine the
impact of CD39 on the in vivo cardiac fibroblast phenotype during cardiac repair and 3) determine the impact of
fibroblast CD39 on in vivo extracellular matrix remodeling during post-MI repair. Secondary Aim: To determine
the impact of CD39 expression extracellular matrix remodeling we will use state-of-the-art MALDI-imaging
mass spectroscopy to define the early and late biosignatures of cardiac ECM remodeling post-MI and
determine the impact of CD39 on ECM remodeling. The outcomes of these studies will reveal the fundamental
pathways by which CD39 regulates post-MI myocardial repair and could allow novel therapeutic approaches
not only to treat fibrotic disorders of the heart, but also of the skin, lungs, bone marrow, liver, or kidneys,
thereby providing an important translational impact.

## Key facts

- **NIH application ID:** 9951089
- **Project number:** 5R01HL127442-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Richard J Gumina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $514,476
- **Award type:** 5
- **Project period:** 2017-07-14 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951089

## Citation

> US National Institutes of Health, RePORTER application 9951089, Ectonucleotidases in ischemic heart disease (5R01HL127442-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9951089. Licensed CC0.

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