Lipid Phosphate Phosphatase 3 as a Novel Atherosclerosis Suppressor

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, 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 and S1P. Analysis of data from a series of genome]wide association studies of coronary artery disease identified a striking association between the PPAP2B locus and myocardial infarction. Our initial analysis indicates that the risk allele is associated with reduced gene expression. Furthermore, we demonstrate that LPP3 is an intrinsic negative regulator of vascular inflammation, suppresses smooth muscle cell proliferation, and promotes endothelial barrier function. These protective effects of LPP3 suggest the testable hypothesis that the 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 validate that the PPAP2B risk allele is associated with reduced expression, provide insight into the mechanism(s) by which LPP3 regulates blood and vascular cell function, and establish its role in the development of atherosclerosis. 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 in the vasculature. Completion of these studies promises to provide valuable insight into the mechanism(s) by which extracellular bioactive lipid mediators influence the development of ischemic heart disease and provide novel and innovative targets to predict, prevent and treat coronary artery disease.