# Lysophosphatidic Acid and Cardiovascular Disease Risk

> **NIH VA I01** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2024 · —

## Abstract

Veterans have a higher incidence of cardiovascular disease than the general population. Valvular diseases
including Calcific Aortic Valve Disease (CAVD) are a particular concern for the aging Veteran Population. At
present, there is no medical therapy to delay or reverse CAVD, and the only treatment is valve replacement for
severe aortic valve stenosis. CAVD involves remodeling of the heart valve tissue as a consequence of
endothelial injury, immune cell infiltration and myofibroblastic / osteogenic differentiation of cells that can
ultimately result in valve leaflet thickening and profound calcification. The fibrosis and calcification stiffen the
leaflets and can result in leaflet fusion that reduces valve opening and causes valve stenosis. Understanding
the molecular mechanisms that drive these changes might lead to the development of much needed therapies
for CAVD. In the past funding period we made mouse models to study the roles of a bioactive lipid,
lysophosphatidic acid (LPA) in cardiovascular and metabolic disease processes. In the course of these studies
we found that mice deficient in the enzyme autotaxin (ATX) that generates LPA were protected from valve
calcification and thickening in a commonly used experimental model. We also observed that mice lacking the
enzyme lipid phosphate phosphatase 3 (LPP3) that can inactivate LPA exhibited greater valve calcification in
this model. These findings are likely translatable to humans because LPP3 levels are decreased during
development of human CAVD while ATX accumulates in the valve tissue and ATX binds to lipoprotein (a)
particles which are themselves associated with CAVD risk. Valvular Interstitial Cells (VICs) are resident cells of
the heart valve tissue that are normally responsible for maintaining the integrity of the heart valves. Pathological
differentiation of these cells to myofibroblastic and osteogenic phenotypes is central to the development of
CAVD. Consistent with literature reports, our preliminary data shows that mouse and human VICs express LPA
selective cell surface receptors. Differentiation of these cells to an osteogenic phenotype and subsequent
calcification can be readily observed in culture medium containing serum which is a rich source of LPA.
Pharmacological antagonism of LPA receptors blocks osteogenic differentiation and calcification of these cells
in culture. In the past funding period we characterized transcriptional circuits that regulate LPP3 expression to
understand why expression is increased in inflammation and decreased by heritable variants that associate with
increased coronary artery disease risk. These studies provide reagents and a framework for understanding why
LPP3 expression is decreased in CAVD. Here we propose to test the broad hypothesis that LPA signaling
promotes CAVD. We will test this hypothesis by using mouse models with cell and tissue type selective
inactivation of LPA receptors, LPP3 and ATX to identify the cell and tissue types involve...

## Key facts

- **NIH application ID:** 10871798
- **Project number:** 5I01BX005637-12
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** ANDREW J MORRIS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871798

## Citation

> US National Institutes of Health, RePORTER application 10871798, Lysophosphatidic Acid and Cardiovascular Disease Risk (5I01BX005637-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10871798. Licensed CC0.

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