# Oxidative stress mediated myocardial lipid dysfunction

> **NIH NIH P20** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2021 · $216,092

## Abstract

Project Abstract 
 Acute myocardial infarction and resulting ischemic heart disease are the single most prevalent cause of 
morbidity and mortality in the western world. While the bioactive glycerophospholipid lysophosphatidic acid 
(LPA) plays a well-known role in atherosclerotic disease, its role in myocardial function remains virtually 
unexplored. Following acute myocardial infarction, serum LPA concentration rises by six-fold over control 
subjects, suggesting LPA may contribute to the pathogenesis of myocardial infarction. LPA production involves 
hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate 
phosphatase-3 (LPP3) catalyzes LPA dephosphorylation to generate lipid products that are not receptor active. 
In this application, we present the first evidence that cardiac ischemia/reperfusion (I/R) injury enhances 
myocardial autotaxin levels and decreases myocardial LPP3 expression, and this is associated with increased 
serum LPA levels. Upon reperfusion, reactive oxygen species production arises as a burst of superoxide from 
mitochondria following I/R injury. The redox-sensitive transcription factor NFAT (a nuclear factor of activated T- 
cells) has been shown to bind to the autotaxin promoter and induce its expression. Similarly, oxidant stress 
may deplete LPP3 levels in the context of I/R injury through reduced LPP3 expression or enhanced LPP3 
degradation. Thus, we hypothesize that I/R injury alters autotaxin and LPP3 expression through mitochondrial 
superoxide production to drive LPA signaling and cardiomyocyte dysfunction. The following interrelated 
specific aims are designed to provide step-wise and in-depth studies in vitro, in vivo, and in experimental 
therapeutics settings. Specific aim 1 will assess the role of myocardial superoxide production in autotaxin 
expression and LPA production in I/R injury metabolism. Specific aim 2 will determine the role of mitochondrial 
superoxide production in LPP3 depletion and LPA production in I/R injury. We could identify whether 
modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect in I/R injury 
models.

## Key facts

- **NIH application ID:** 10086880
- **Project number:** 5P20GM121307-04
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Manikandan Panchatcharam
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $216,092
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086880

## Citation

> US National Institutes of Health, RePORTER application 10086880, Oxidative stress mediated myocardial lipid dysfunction (5P20GM121307-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10086880. Licensed CC0.

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