# Targeting cardiac fibroblast-myocyte cross talk to enhance heart function after cardiac injury

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $546,000

## Abstract

Project Summary/Abstract
Cardiac repair following ischemic myocardial injury involves a carefully orchestrated set of cellular events. The
cardiac cell population substantially changes after cardiac injury with infiltration of initially neutrophils, then
macrophages and robust proliferation of fibroblasts and endothelial cells. Cell-cell cross talk undoubtedly
affects cardiac wound healing but little is known about whether cell-cell cross talk can be targeted for
enhancing cardiac repair. In this proposal, we identify an unusual cross talk between myocytes and non-
myocytes that regulates cardiac wound healing. We demonstrate that cardiac fibroblasts dramatically
upregulate the protein ENPP1 (ectonucleotide pyrophosphatase 1) following ischemic cardiac injury. ENPP1
hydrolyzes extracellular ATP and we show that ATP hydrolytic products induces myocytes to release
metabolites that are pro-inflammatory and induce cell death of various non-myocyte cells regulating wound
healing such as macrophages, endothelial cells, fibroblasts and smooth muscle cells. We identify such
myocyte secreted pro-inflammatory metabolites and investigate molecular mechanisms of action of such
metabolites on non-myocyte cells. We provide preliminary data that genetic deletion of ENPP1 in cardiac
fibroblasts dramatically ameliorates post injury heart function and is associated with decreased scarring and
decreased post injury cardiac dilatation. We identify small molecule inhibitors of ENPP1 as well as monoclonal
antibodies targeting ENPP1 and demonstrate that pharmacologic targeting of ENPP1 can serve as a
therapeutic strategy for post infarction cardiac remodeling. These observations form a rational basis for
investigating in depth the physiological significance of ENPP1 mediated myocyte-non myocyte cross talk in
cardiac repair and determine whether pharmacologic targeting of ENPP1 mediated fibroblast-non myocyte
cross talk is potentially a therapeutic strategy for ischemic cardiac injury.

## Key facts

- **NIH application ID:** 10050499
- **Project number:** 1R01HL149658-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Arjun Deb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $546,000
- **Award type:** 1
- **Project period:** 2020-09-02 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050499

## Citation

> US National Institutes of Health, RePORTER application 10050499, Targeting cardiac fibroblast-myocyte cross talk to enhance heart function after cardiac injury (1R01HL149658-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10050499. Licensed CC0.

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