# Alcohol mediated myocardial lysophosphatidic acid signaling

> **NIH NIH R21** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2021 · $173,375

## Abstract

Abstract
 Chronic long-term abuse of alcohol leads to myocardial dysfunction and results in heart failure. The
mechanism by which alcohol causes cardiac damage remains unclear. Mitochondrial dysfunction plays a
significant role in the development and complications of alcoholic cardiomyopathy due to changes in cellular
lipid levels. In cell culture models, elevated lysophosphatidic acid (LPA) signaling induces markers of
cardiomyocyte dysfunction (enhanced Atrial natriuretic peptide [ANP] and brain natriuretic peptide [BNP]
expression). Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted
enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes lysophosphatidic acid
dephosphorylation to generate lipid products that are not receptor active. In this application, we present the
first evidence that heavy alcohol consumption enhances the myocardial autotaxin levels and decreases LPP3
expression, and this is associated with increased lysophosphatidic acid signaling. We speculate that upon
heavy alcohol consumption, the redox-sensitive transcription factor NFAT (a nuclear factor of activated T-cells)
bind to the autotaxin promoter and induce its expression. Furthermore, alcohol transactivates microRNA-92a,
which is a negative regulator of LPP3. Thus, we hypothesize that heavy alcohol consumption alters autotaxin
and LPP3 expression to drive lysophosphatidic acid signaling and myocardial 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 alcohol-induced autotaxin expression
and lysophosphatidic acid production in the myocardium. Specific Aim 2 will determine the role of alcohol-
mediated LPP3 depletion and lysophosphatidic acid regulation in the myocardium. We could identify whether
modulation of extracellular versus intracellular antioxidant status confers a differential protective effect upon
exposure to heavy alcohol consumption. This study will not only extend our understanding of alcohol-
autotaxin-LPA-LPP3 mediated cardiac failure but will also identify novel targets for future clinical interventions.

## Key facts

- **NIH application ID:** 10149211
- **Project number:** 5R21AA026708-02
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Manikandan Panchatcharam
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $173,375
- **Award type:** 5
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149211

## Citation

> US National Institutes of Health, RePORTER application 10149211, Alcohol mediated myocardial lysophosphatidic acid signaling (5R21AA026708-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10149211. Licensed CC0.

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