Lysophosphatidic acid (LPA) is an essential bioactive phospholipid mediator that regulates a range of developmental and physiological processes which are emerging as targets for a new class of molecular therapeutics. In the cardiovascular system, LPA is poised to serve as a mediator of atherothrombotic disease: it is abundant in atherosclerotic plaque, increases during acute myocardial infarction, triggers phenotypic responses in smooth muscle cells, and disrupts endothelial integrity. We and others have demonstrated that LPA promotes both the development of intimal hyperplasia following injury and atherosclerosis in experimental models. Lipid phosphate phosphatase 3 (LPP3), encoded by the PPAP2B gene, is an integral membrane enzyme that regulates the bioavailability of LPA. We have recently demonstrated that LPP3 is an intrinsic negative regulator of vascular inflammation, suppresses smooth muscle cell proliferation, and promotes endothelial barrier function likely by limiting LPA signaling. Analysis of data from a series of genome-wide association studies of coronary artery disease (CAD) identified a striking association between the PPAP2B locus and myocardial infarction. We provide evidence that CAD-risk associated PPAP2B variant disrupts an intronic enhancer that increases transcription of the gene and LPP3 expression in ox-LDL stimulated macrophages. These findings suggest the testable hypothesis that LPP3 functions as an atherosclerosis suppressor and that reduced PPAP2B gene expression aggravates cellular events underlying atherosclerosis and increases the likelihood of myocardial infarction. In this proposal, we will define the role of LPP3 in the development of atherosclerosis, provide insight into the molecular mechanism(s) involved, and validate the predicted risk allele associated with CAD in humans. We are uniquely well-prepared to achieve these goals based on our expertise in bioactive lipid signaling and the tools we have amassed to study LPP3. Completion of these studies promises to provide valuable insight into the mechanism(s) by which extracellular bioactive lipid mediators influence the development of atherosclerosis and provide novel and innovative targets to predict, prevent and treat CAD.

Public Health Relevance

Ischemic heart disease is a leading cause of death in the United States. Genetic variation in the gene encoding lipid phosphate phosphatase 3 (LPP3), an enzyme that regulates the bioavailability of lysophospholipids, was recently identified to predict the development of coronary artery disease and acute myocardial infarction. We propose that LPP3 functions as an atherosclerosis suppressor. Completion of our work will define mechanism(s) involved and may implicate bioactive lipid mediators in the development of ischemic heart disease, which will ultimately provide novel and innovative targets to predict, prevent and treat coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL120507-01A1
Application #
8888525
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2015-04-01
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$521,134
Indirect Cost
$174,578
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Gomez-Cambronero, J; Morris, A J; Henkels, K M (2017) PLD Protein-Protein Interactions With Signaling Molecules and Modulation by PA. Methods Enzymol 583:327-357
Keune, Willem-Jan; Hausmann, Jens; Bolier, Ruth et al. (2016) Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling. Nat Commun 7:11248
Murphy, Margaret O; Petriello, Michael C; Han, Sung Gu et al. (2016) Exercise protects against PCB-induced inflammation and associated cardiovascular risk factors. Environ Sci Pollut Res Int 23:2201-11
Morris, Andrew J; Smyth, Susan S (2016) Regulation of Lysophosphatidic Acid Metabolism and Signaling by Lipoproteins. Arterioscler Thromb Vasc Biol 36:2029-30
Vogt, Johannes; Yang, Jenq-Wei; Mobascher, Arian et al. (2016) Molecular cause and functional impact of altered synaptic lipid signaling due to a prg-1 gene SNP. EMBO Mol Med 8:25-38
Li, Jing; Song, Jun; Zaytseva, Yekaterina Y et al. (2016) An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature 533:411-5
Mueller, Paul; Ye, Shaojing; Morris, Andrew et al. (2015) Lysophospholipid mediators in the vasculature. Exp Cell Res 333:190-4
Siow, Deanna; Sunkara, Manjula; Dunn, Teresa M et al. (2015) ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis. J Lipid Res 56:898-908
Abdel-Latif, Ahmed; Heron, Paula M; Morris, Andrew J et al. (2015) Lysophospholipids in coronary artery and chronic ischemic heart disease. Curr Opin Lipidol 26:432-7
Morris, Andrew J; Smyth, Susan S (2014) Lipid phosphate phosphatases: more than one way to put the brakes on LPA signaling? J Lipid Res 55:2195-7