# Targeting Macrophage Lysosome Biogenesis Program in Cardiomyopathy and Heart Failure

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2020 · —

## Abstract

Heart failure due to myocardial infarction (MI) is leading cause of death in the United States. Infiltration of
peripheral monocytes and resident cardiac macrophages are postulated to play a dual role in the post-MI
period, 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. Persistence of pro-inflammatory
macrophages correlates with maladaptive left ventricular remodeling and progressive heart failure. Obesity and
resultant (type II) diabetes have reached epidemic proportions and predispose to development of heart failure
by provoking development of lipid overload in myocardium, i.e. cardiac lipotoxicity; and by promoting coronary
artery disease in concert with other risk factors such as hypertension, hyperlipidemia and a sedentary lifestyle.
Early macrophage recruitment drives inflammation and promotes development of lipotoxic cardiomyopathy in
animal models. These observations indicate that strategies to modulate macrophage inflammatory phenotype
may be of therapeutic benefit. Emerging data point to a critical role for lysosomal function in macrophage
inflammatory responses. TFEB and TFE3, two closely related family members have been demonstrated to
function as the master transcriptional activators of the lysosomal biogenesis program in macrophages, acting
in a mutually redundant fashion; and activation of TFEB and TFE3 is essential for sustaining macrophage
phagocytosis. Our preliminary and published findings demonstrate that macrophage TFEB expression
attenuates post-MI remodeling and protects against lipotoxic cell death. We have previously found that
intermittent fasting activates TFEB to stimulate lysosome function in the myocardium and attenuate cardiac
myocyte death during MI. Our preliminary data demonstrate that intermittent fasting rescues mortality and
attenuates the inflammatory response to prevent cardiomyopathy and heart failure in MHC-ACSL1 mice with
cardiac lipotoxicity due to transgenic expression of acylCoA-synthetase 1 (ACSL1); suggesting that intermittent
fasting may also modulate macrophage lysosome function and the inflammatory response. In this proposal, we
hypothesize that TFEB/TFE3-mediated transcriptional regulation of the macrophage lysosome biogenesis
program is critical to attenuate inflammatory responses in the myocardium, post-MI and under lipotoxic stress;
and can be harnessed therapeutically to prevent heart failure. In aim 1, we will examine the role of the
macrophage lysosome biogenesis program in preventing post-MI heart failure in a closed chest model of
cardiac ischemia-reperfusion injury and attenuating cardiomyopathy secondary to lipotoxicity in the MHC-ACS
mouse model. In aim 2, we will examine the mechanisms for TFEB/TFE3-mediated modulation of macrophage
phenotype. In aim 3, we will evaluate the efficacy of trehalose, an activator of TFEB/TFE3-induced lysosomal
biogenesis, in at...

## Key facts

- **NIH application ID:** 9898259
- **Project number:** 5I01BX004235-03
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Abhinav Diwan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898259

## Citation

> US National Institutes of Health, RePORTER application 9898259, Targeting Macrophage Lysosome Biogenesis Program in Cardiomyopathy and Heart Failure (5I01BX004235-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898259. Licensed CC0.

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