# Mitophagy pathways in cellular cross-talk in the myocardium

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2024 · —

## Abstract

Myocardial infarction (MI) with resultant ischemic cardiomyopathy and heart failure rank among the leading
causes of morbidity and mortality among Veterans in the United States. In ischemic cardiomyopathy, sustained
and unregulated inflammatory signaling is recognized as a driver of heart failure pathogenesis. Therefore,
understanding the crosstalk between immune cells and cardiac myocytes has the potential to inform
therapeutic strategies. Immune cells in the myocardium affect cardiac myocyte structure and function via cell
autonomous and non-autonomous mechanisms. Cardiac macrophages are increasingly recognized as the
dominant immune cell type driving pro-inflammatory signaling under stress. On the other hand, studies also
point to critical homeostatic roles for resident cardiac macrophages in maintenance of cardiac structure and
function. Indeed, in the post-MI period, infiltrated peripheral monocytes differentiate into macrophages and are
postulated to play a dual role in concert with the resident cardiac macrophages, characterized by pro-
inflammatory signaling and phagocytic removal of dead cells in the early phase and a shift towards anti-
inflammatory signaling to promote reparative phase. In published VA MERIT-supported studies, we have
uncovered evidence for impaired lysosome function in macrophages as a driver of pro-inflammatory signaling.
Our studies further demonstrated the efficacy of stimulating the macrophage lysosome biogenesis program by
activation of TFEB, a master regulator of autophagy-lysosome pathway, in engendering a phenotypic switch in
macrophages and promoting post-MI healing. In parallel studies, we have uncovered an essential role for
TRAF2 in cardiac myocytes in executing physiologic mitophagy, a selective lysosomal degradative pathway
that removes damaged mitochondria to prevent mitochondrial DNA leak and suppress sterile inflammation in
the myocardium. In this proposal, we will examine the role of TRAF2 and mitophagy in macrophages in
shaping myocardial homeostasis; to understand how targeting mitophagy affects cellular crosstalk in the
myocardium in homeostasis and under stress. Our preliminary data suggest the hypothesis that TRAF2 plays
an essential role in macrophages by facilitating macrophage mitophagy and generation of 25-
hydroxycholesterol to restrain inflammasome activation, to maintain myocardial homeostasis. Indeed, our
preliminary studies demonstrate that inducible macrophage TRAF2 ablation using genetic approaches induces
cardiac myocyte hypertrophy, left ventricular hypertrophy and systolic dysfunction, and increased inflammatory
cell infiltration in the myocardium. We have acquired reagents and developed collaborations to test the
hypothesis. In specific aim, we will evaluate the consequences of loss of TRAF2 in macrophages on
inflammatory signaling. In specific aim 2, we will evaluate the consequences of loss of TRAF2 in macrophages
on cardiac myocyte mitophagy, and perform mechanistic studies to ...

## Key facts

- **NIH application ID:** 10721828
- **Project number:** 5I01BX005981-02
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Abhinav Diwan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721828

## Citation

> US National Institutes of Health, RePORTER application 10721828, Mitophagy pathways in cellular cross-talk in the myocardium (5I01BX005981-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10721828. Licensed CC0.

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