# Apolipoprotein M: a novel regulator of myocardial Autophagy

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $588,733

## Abstract

PROJECT SUMMARY/ABSTRACT
Heart failure (HF) is a major cause of mortality worldwide, and identifying novel therapies to treat HF
represents an urgent clinical need. The long-term vision of my laboratory is that apolipoproteins can be used to
treat HF. We have discovered that reduced circulating levels of apolipoprotein M (ApoM) are associated with
increased mortality in human HF. Each standard deviation reduction in ApoM is associated with a doubling of
mortality risk in HF, an association that is independent of B-type natriuretic peptide, coronary artery disease,
and other known risk factors. ApoM is made almost exclusively by the liver, secreted by hepatocytes, and
binds the bioactive lipid sphingosine-1-phosphate (S1P) on HDL particles in the circulation, ultimately
activating G-protein coupled S1P receptors on various cell types; however, the precise mechanism by which
ApoM may increase HF survival is unknown.
To understand mechanisms of cardioprotection by ApoM, we utilized a doxorubicin cardiotoxicity (DoxTox)
model. Dox is utilized to treat multiple human cancers, but its use is limited by DoxTox and long-term HF. We
have discovered that Dox reduces ApoM in humans and mice. In DoxTox models, increasing ApoM improves
survival and prevents Dox-induced cardiac dysfunction. In a clinically relevant acute myeloid leukemia model,
preliminary studies indicate ApoM does not interfere with Dox anti-cancer efficacy.
Our preliminary data suggest that ApoM attenuates Dox-induced autophagic impairment in the myocardium.
We find ApoM increases autophagic flux and preserves nuclear transcription factor EB (TFEB), a master
regulator of autophagy and lysosomal biogenesis implicated in multiple cardiomyopathies. Our data suggest
ApoM-driven autophagy and preservation of nuclear TFEB are protective mechanisms generalizable to other
cardiomyopathies. This R01 proposal tests the hypothesis that ApoM, via canonical S1P signaling, enhances
myocardial autophagy and preserves nuclear TFEB to attenuate DoxTox. Aim 1 tests whether hepatic S1P
production is required for ApoM-mediated myocardial autophagy; Aim 2 tests whether the S1P receptor at the
level of cardiomyocyte is required for autophagy, and Aim 3 tests whether cardiomyocyte TFEB is required for
the cardioprotective effects of ApoM. Aim 3 also utilizes the innovative technique of CUT&RUN sequencing to
determine whether ApoM directs TFEB to specific transcriptional targets, which will help elucidate or confirm
other pathways downstream of TFEB directed by ApoM. Success of these aims will identify mechanisms by
which ApoM can attenuate DoxTox and improve outcomes in HF.

## Key facts

- **NIH application ID:** 10908403
- **Project number:** 5R01HL155344-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ali Javaheri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $588,733
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908403

## Citation

> US National Institutes of Health, RePORTER application 10908403, Apolipoprotein M: a novel regulator of myocardial Autophagy (5R01HL155344-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10908403. Licensed CC0.

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