# The role of bioactive lipids in CMC-induced myocardial repair.

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2022 · $385,000

## Abstract

A variety of sterile diseases, including myocardial infarction (MI) and subsequent repair, involve the
immune system. Although unresolved inflammation exacerbates heart failure, depletion of macrophages in the
infarcted myocardium leads to left ventricular (LV) rupture and death. Thus, indiscriminate immunosuppression
is not a viable approach. Nevertheless, persistent inflammation in the failing heart must be addressed.
Unfortunately, significant barriers to progress remain because we do not know how immune cells regulate
myocardial repair and what determines their harmful versus salutary actions. Cell therapy provides a unique
opportunity for understanding how immune cells contribute to myocardial repair, and recent findings implicate
macrophages as direct contributors to cell therapy-mediated myocardial repair. Although few injected cells
survive long-term in the recipient, common benefits include reduction of fibrosis, enhanced angiogenesis, and
improvement in LV function. These improvements occur independently of differentiation of the injected cells
into cardiomyocytes, suggesting that cell therapy must recruit endogenous repair mechanisms; however, these
mechanisms remain unidentified. Our preliminary data show that injection of cardiac mesenchymal cells
(CMCs) into the infarcted heart promotes accumulation of reparative macrophages, decreases fibrosis, and
improves LV function. Co-culture of CMCs with macrophages favors a reparative macrophage program, and it
may be due to CMC-derived bioactive lipids—such as prostaglandins, leukotrienes, and resolvins— which offer
testable explanations of the `paracrine hypothesis' of cell-mediated repair. Thus, we propose that CMCs recruit
monocytes and activate reparative macrophages, which promote favorable anti-fibrotic cardiac remodeling and
improve cardiac function in the infarcted heart. In the current project we will determine the capacity for the
bioactive lipid synthesis and secretion in CMCs. Mass spectrometry will be performed to explore the role of
Cox and Lox pathways in bioactive lipid synthesis in CMCs. Moving forward we will ascertain the role bioactive
lipids in macrophage recruitment and their reparative function, with the particular focus on macrophage BLT-1
receptor and its CMC-derived ligands. Finally, we will determine the reparative effect of CMCs with enhanced
bioactive lipid synthesis in mouse model of HF. This project will be the first systematic analysis of bioactive
lipid synthesis profile in reparative CMCs. This project will provide novel insights into not only pathways of
bioactive lipid synthesis in CMC but also the mechanisms regulating cell therapy-mediated myocardial repair.

## Key facts

- **NIH application ID:** 10369658
- **Project number:** 5R01HL141191-04
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Marcin Wysoczynski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369658

## Citation

> US National Institutes of Health, RePORTER application 10369658, The role of bioactive lipids in CMC-induced myocardial repair. (5R01HL141191-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10369658. Licensed CC0.

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