Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are essential bioactive lysolipid mediators that regulate a range of developmental and physiological processes and 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, present in the blood, produced by activated platelets, triggers phenotypic responses in smooth muscle cells, and potentiates platelet activation. Exposure of LPA during atherosclerotic plaque rupture/erosion has been proposed as a key modulator of platelet thrombosis. We report a novel pathway for regulation of platelet LPA responses that involves recruitment of the lysophospholipase D enzyme, autotaxin, responsible for LPA production to activated platelets. We have also found that LPA inhibits mouse platelet function, and that approximately 20% of human volunteers also lack a stimulatory response to LPA. We have evidence that this inhibitory LPA-signaling pathway confers vascular protection from thrombosis in mice and potentially from atherosclerotic disease in humans. We suggest that a therapeutic strategy directed at blocking stimulatory platelet LPA responses while promoting inhibitory ones could result in beneficial anti-thrombotic effects. Implementation of this strategy requires the molecular characterization of platelet LPA responses and proof of a role for circulating or locally produced LPA in regulating hemostasis and thrombosis. The broad goal of this proposal is to provide mechanistic insight essential for establishing LPA signaling as a viable anti-thrombotic target. We will take advantage of the differences in murine and human platelet LPA responses to identify the receptor(s) responsible for LPA signaling in mice and humans and then generate a transgenic mouse with platelet-specific expression of a stimulatory LPA receptor that phenocopies the human LPA response so that processes of relevance to human disease can be studied in a small animal mode. 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 LPA in the vasculature. Completion of these studies promises to provide valuable insight into regulation of platelet function and may have exciting implications for the development of novel anti-thrombotic strategies that target LPA signaling.

Public Health Relevance

Atherothrombotic vascular disease is a leading cause of death in the United States. Blood platelets are essential for acute thrombotic events, such as heart attacks and strokes, and also contribute to local and systemic inflammation. This research project seeks to understand how the production of a class of pro-inflammatory lipid molecules is influenced by platelets and how the lipids affect platelet function. Completion of the work will provide new insights into pathways that could be targeted to prevent and treat arterial thrombosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078663-08
Application #
8485634
Study Section
Special Emphasis Panel (ZRG1-VH-E (02))
Program Officer
Hasan, Ahmed AK
Project Start
2004-09-24
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$344,365
Indirect Cost
$108,745
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Smyth, Susan S; Mueller, Paul; Yang, Fanmuyi et al. (2014) Arguing the case for the autotaxin-lysophosphatidic acid-lipid phosphate phosphatase 3-signaling nexus in the development and complications of atherosclerosis. Arterioscler Thromb Vasc Biol 34:479-86
Totani, Licia; Piccoli, Antonio; Dell'Elba, Giuseppe et al. (2014) Phosphodiesterase type 4 blockade prevents platelet-mediated neutrophil recruitment at the site of vascular injury. Arterioscler Thromb Vasc Biol 34:1689-96
Panchatcharam, Manikandan; Salous, Abdel K; Brandon, Jason et al. (2014) Mice with targeted inactivation of ppap2b in endothelial and hematopoietic cells display enhanced vascular inflammation and permeability. Arterioscler Thromb Vasc Biol 34:837-45
Ren, H; Panchatcharam, M; Mueller, P et al. (2013) Lipid phosphate phosphatase (LPP3) and vascular development. Biochim Biophys Acta 1831:126-32
Morris, Andrew J; Smyth, Susan S (2013) Lysophosphatidic acid and cardiovascular disease: seeing is believing. J Lipid Res 54:1153-5
Nagareddy, Prabhakara; Smyth, Susan S (2013) Inflammation and thrombosis in cardiovascular disease. Curr Opin Hematol 20:457-63
Panchatcharam, Manikandan; Miriyala, Sumitra; Salous, Abdelghaffar et al. (2013) Lipid phosphate phosphatase 3 negatively regulates smooth muscle cell phenotypic modulation to limit intimal hyperplasia. Arterioscler Thromb Vasc Biol 33:52-9
Karapetyan, Anush V; Klyachkin, Yuri M; Selim, Samy et al. (2013) Bioactive lipids and cationic antimicrobial peptides as new potential regulators for trafficking of bone marrow-derived stem cells in patients with acute myocardial infarction. Stem Cells Dev 22:1645-56
Federico, Lorenzo; Ren, Hongmei; Mueller, Paul A et al. (2012) Autotaxin and its product lysophosphatidic acid suppress brown adipose differentiation and promote diet-induced obesity in mice. Mol Endocrinol 26:786-97
Cheng, Hsin-Yuan; Dong, Anping; Panchatcharam, Manikandan et al. (2012) Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling. Arterioscler Thromb Vasc Biol 32:24-32

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