# Novel sphingolipid metabolites in myocardial ischemia

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $388,125

## Abstract

Project Summary
 Ischemic cardiomyopathy is the leading cause of death in the world and affects approximately 1% to 2%
of the general population. Sphingolipids, a lipid class bearing signaling properties, have been implicated in
numerous cardiac pathologies. Sphingolipids are formed by serine palmitoyltransferase, a heterodimeric enzyme
comprised of the subunits Sptlc1 and Spltc2. This heterodimer combines serine and palmitoyl-CoA to generate
dihydrosphingosine, which serves as a scaffold for generation of all downstream sphingolipids (e.g. ceramides,
sphingomyelins, glycosphingolipids, sphingosine-1-phosphate, etc.). Despite their implication in pathology,
sphingolipids are required by all eukaryotic cells; depletion of Sptlc2 in cardiomyocytes led to cardiac dysfunction
(Lee, SY et al. 2012 J. Biol. Chem). However, previously identified a novel pool of myocardial sphingolipids
These lipids arise from a dimerization of Sptlc1 with a novel SPT subunit, Sptlc3. We previously published work
showing that Sptlc3 is strongly induced in diabetic cardiomyopathy. Here we show that Sptlc3 is also induced in
human ischemic HF and in mouse models of both acute and chronic ischemia. The products of the Sptlc1/3
complex, which we showed are pro-apoptotic, also increase in human ischemic heart and mouse models.
Therefore, we propose that the canonical sphingolipids derived from Sptlc1/2 heterodimer are homeostatic, but
in some cardiac insults (lipotoxicity, ischemia) Sptlc3 is induced, changing the intracellular sphingolipidome and
leading to deleterious outcomes. This would present the opportunity for therapeutic intervention directed toward
atypical, Sptlc3-derived sphingolipids, leaving the homeostatic sphingolipid pool intact.
 The scientific premise behind our hypothesis is that sphingolipid metabolism could be targeted to prevent
ischemic injury. Our hypothesis is that ischemia induces these atypical sphingolipids, or a subset thereof, which
promote apoptosis and are thereby toxic to cardiomyocytes, and that blocking their production will attenuate
ischemic injury. This will be tested in 3 aims: 1-to test whether cardiomyocyte-specific depletion of Sptlc3
will attenuate ischemic injury and/or heart failure in acute or chronic ischemia in mice, 2-to determine the
mechanism(s) of Sptlc3 upregulation in acute vs. chronic ischemia and identify the downstream
metabolic pathways and resulting subset of atypical lipids that are produced; and 3-to determine the
mechanism(s) by which the atypical lipids induce apoptosis. This proposal will establish the role of non-
canonical sphingolipids in ischemic cardiomyopathy and will lay the foundation for further research on potential
targeting of the pathway as an innovative therapeutic option to prevent ischemic injury and heart failure and
improve patient outcome.

## Key facts

- **NIH application ID:** 10073151
- **Project number:** 1R01HL151243-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Lauren Ashley Cowart
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,125
- **Award type:** 1
- **Project period:** 2020-07-07 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073151

## Citation

> US National Institutes of Health, RePORTER application 10073151, Novel sphingolipid metabolites in myocardial ischemia (1R01HL151243-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073151. Licensed CC0.

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