Lipid phosphate phosphatase 3 as a novel atherosclerosis suppressor

 描述（由申请人提供）：溶血磷脂酸（LPA）是一种重要的生物活性磷脂介质，可调节一系列发育和生理过程，这些过程正在成为一类新的分子治疗剂的靶点。在心血管系统中，LPA准备充当动脉粥样硬化血栓形成疾病的介质：它在动脉粥样硬化斑块中丰富，在急性心肌梗死期间增加，触发平滑肌细胞中的表型反应，并破坏内皮完整性。我们和其他人已经证明LPA在实验模型中促进损伤后内膜增生和动脉粥样硬化的发展。由PPAP 2B基因编码的脂质磷酸酶3（LPP 3）是调节LPA的生物利用度的整合膜酶。我们最近证明，LPP3是血管炎症的内在负调节因子，抑制平滑肌细胞增殖，并可能通过限制LPA信号传导促进内皮屏障功能。对冠状动脉疾病（CAD）的一系列全基因组关联研究的数据进行分析，发现PPAP2B基因座与心肌梗死之间存在显著关联。我们提供的证据表明，CAD风险相关的PPAP2B变异破坏了内含子增强子，增加了基因的转录和氧化低密度脂蛋白刺激的巨噬细胞中的LPP3表达。这些发现提示了一个可验证的假设，即LPP3作为动脉粥样硬化抑制剂发挥作用，PPAP2B基因表达降低会加重动脉粥样硬化相关的细胞事件，并增加心肌梗死的可能性。在这项提案中，我们将定义LPP3在动脉粥样硬化发展中的作用，提供有关分子机制的见解，并验证与人类CAD相关的预测风险等位基因。基于我们在生物活性脂质信号传导方面的专业知识和我们积累的研究LPP3的工具，我们为实现这些目标做好了独一无二的充分准备。这些研究的完成有望为细胞外生物活性脂质介质影响动脉粥样硬化发展的机制提供有价值的见解，并为预测、预防和治疗CAD提供新的和创新的靶点。

 DESCRIPTION (provided by applicant): 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.