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  • Lipid Phosphate Phosphatase 3 (LPP3) Terminates Lysophosphatidic Acid (LPA) Pathologic Signaling in Vascular Wall Cells but Does not Mediate Systemic Elimination of LPA from Plasma

    Final Number:

    Abdel Salous MS MD/PhD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2014 Annual Meeting

    Introduction: The bioactive lipid lysophosphatidic acid (LPA) is present in most biological fluids including plasma and cerebrospinal fluid at a concentration of ~0.1-1uM. LPA has a number of developmental, physiological, and pathophysiological actions in the vasculature including cellular differentiation, atherothrombosis, inflammation, response to injury, and vascular permeability. LPA has pleiotropic effects in vascular wall cells including vascular endothelial and smooth muscle cell functions, with potential roles in neurovascular disease. Pathways for synthesis and signaling of LPA in the vasculature have been extensively studied but mechanisms responsible for its elimination are less well understood. The broad goal of my dissertation research is to identify the role of the enzyme termed lipid phosphate phosphatase 3 (LPP3) in the termination of pathopathologic LPA signaling and elimination in vascular models of injury.

    Methods: We used animal models targeted genetic inactivation of LPP3 in vascular endothelial and smooth muscle cells and modified surgical models to study the elimination of LPA from the plasma and the mechanisms mediating this process. Our methods included loss and gain of function approaches, an in vitro expression system, synthetic lysophospholipid mimetics, and HPLC/tandem mass spectrometry assays.

    Results: Briefly, our results indicated that LPP3 played a critical role in attenuating LPA signaling mediating the pathological processes of intimal hyperplasia and vascular permeability/leak in mouse models of disease. Additionally, enzymatic inactivation contributed by LPP3 or other enzymes did not play a key role in the rapid elimination of LPA plasma. Instead, transcellular uptake by hepatic non-parenchymal cells was the predominant mechanism for elimination of LPA and related analogs.

    Conclusions: These findings provide potential mechanistic insights for recent genome wide association studies reporting on the association of a polymorphism of LPP3 with coronary artery disease and strong implications for similar roles of LPA signaling in cerebrovascular disease and the design of future lysophophoslipid therapeutic mimetics for vascular injury.

    Patient Care: Basic science knowledge gained from this research will enhance our understanding about the role of lysophospholipid signaling in the vasculature and pave the way to developing novel therapeutics that will limit the extent of disease states exacerbated by lysophospholipid signaling in the context of injury.

    Learning Objectives: LPA signaling is a key pathway for vascular disease with promising therapeutics in vascular neurosurgery as well as potential applications in neurotrauma and neuro-oncology.

    References: 1: Panchatcharam M, Salous AK, Brandon J, Miriyala S, Wheeler J, Patil P, Sunkara M, Morris AJ, Escalante-Alcalde D, Smyth SS. Mice with targeted inactivation of ppap2b in endothelial and hematopoietic cells display enhanced vascular inflammation and permeability. Arterioscler Thromb Vasc Biol. 2014 Apr;34(4):837-45. doi: 10.1161/ATVBAHA.113.302335. Epub 2014 Feb 6. PubMed PMID: 24504738. 2: Salous AK, Panchatcharam M, Sunkara M, Mueller P, Dong A, Wang Y, Graf GA, Smyth SS, Morris AJ. Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice. J Lipid Res. 2013 Oct;54(10):2775-84. doi: 10.1194/jlr.M039685. Epub 2013 Aug 15. PubMed PMID: 23948545; PubMed Central PMCID: PMC3770090. 3: Panchatcharam M, Miriyala S, Salous A, Wheeler J, Dong A, Mueller P, Sunkara M, Escalante-Alcalde D, Morris AJ, Smyth SS. Lipid phosphate phosphatase 3 negatively regulates smooth muscle cell phenotypic modulation to limit intimal hyperplasia. Arterioscler Thromb Vasc Biol. 2013 Jan;33(1):52-9. doi: 10.1161/ATVBAHA.112.300527. Epub 2012 Oct 25. PubMed PMID: 23104851; PubMed Central PMCID: PMC3524385.

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