# Coordination of cardiac inflammation/remodeling in heart failure by myeloid catabolism of purinergic DAMPs

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

ABSTRACT: Despite advances in treatment and prevention, millions of Americans still suffer from heart failure
(HF), and acute HF(AHF) is the leading cause of hospitalization in the veteran population. Although
hemodynamic, immune, and mechanical stress are associated with HF, how the heart responds to these
stresses and how they together drive HF remain largely unknown. Extracellular purinergic catabolism is an
evolutionarily conserved system that regulates both vascular and immune stress responses. In the heart,
stressed cardiomyocytes (CM) release purines (including adenosine triphosphate [ATP]) to the extracellular
environment as part of a damage associated molecular pattern (DAMP) response. CD39 is a surface
ectonucleotidase that catabolizes ATP. Our analysis of genetic variants in the UK Biobank suggests that CD 39
deficiency is associated with incident HF. Mechanistically, our preliminary data indicate that stressed CM release
ATP in response to a variety of cardiac stresses, and that CD39 is expressed on macrophages (Mϕ). In clinical
AHF, we have found that blood inflammatory markers are increased on admission and that CD39 is expressed
in circulating monocytes from AHF patients. Furthermore, our laboratory has found that mice deficient in CD39
only in macrophages have increased fibrosis in a model of pressure-overload HF, revealing a novel mechanism
through which macrophage CD39 shapes pathologic cardiac remodeling. The requirement for CM-macrophage
cooperation to dissipate extracellular ATP suggests that the extracellular breakdown of ATP could be a critical
integrator of stress responses in HF. The objective of this proposal is to define the molecular mechanisms
through which the extracellular ATP catabolism orchestrates inflammation and pathologic cardiac remodeling
and to define the functional properties of CD39+ monocytes in murine models and patients with AHF. Specifically,
this project will (1) delineate the mechanisms through which the catabolism of extracellular ATP modulates CM
and macrophage hemodynamic, immune, and mechanical stress responses; (2) define how macrophage
catabolism of ATP regulates cardiac inflammation and fibrosis in two murine models; and (3) elucidate how
hypervolemia associated with AHF modulates the levels of circulating DAMPs/immune mediators and CD39+
monocytes and how these immunotypes evolve during the treatment of AHF. The experiments proposed here
will test the hypothesis that extracellular ATP catabolism by Mϕ CD39 coordinates cardiac stress responses and
that the inability to breakdown extracellular ATP promotes inflammation and pathologic cardiac remodeling, a
vicious cycle that accelerates HF. This proposal leverages the power of novel macrophage-specific transgenic
murine models, targeted proteomics/transcriptomics, and mass cytometry to define the ATP-mediated cell-cell
interactions that govern cardiac remodeling and inflammation in cell/murine models and patients with AHF.

## Key facts

- **NIH application ID:** 10701341
- **Project number:** 1I01CX002560-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Sascha Nilu Goonewardena
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701341

## Citation

> US National Institutes of Health, RePORTER application 10701341, Coordination of cardiac inflammation/remodeling in heart failure by myeloid catabolism of purinergic DAMPs (1I01CX002560-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10701341. Licensed CC0.

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