Lysophosphatidic acid and cardiovascular disease risk

退伍军人的心血管疾病发病率高于普通人群。心血管 疾病风险由环境和遗传因素引起。我们研究的主要目标是了解 这些因素如何相互作用以确定整体疾病风险。在本奖项的当前资助期内，我们研究了 编码脂质磷酸磷酸酶3（LPP 3）的PLPP 3基因的遗传变异如何与 遗传性冠心病风险我们发现，疾病风险相关的基因座内的最后内含子， 该基因降低了该基因在血液和血管细胞中的表达，并且小鼠中PLPP 3缺乏导致 加速动脉粥样硬化我们的研究结果支持PLPP 3作为“动脉粥样硬化”的概念。 抑制”基因和降低该基因表达遗传变异会增加心脏病的风险。 LPP 3是一种完整的膜细胞表面酶，可以使生物活性脂质去磷酸化和降解 调解员这些LPP 3底物之一，溶血磷脂酸（LPA）作用于多种血液和血管 细胞，以促进炎症和心血管疾病的进展。在小鼠中，遗传或药理 靶向LPA调节动脉粥样硬化。在我们的小鼠研究中，LPP 3缺乏与 血液和血管组织中LPA水平升高。这些结果支持了我们的总体假设 LPA的去磷酸化和失活是LPP 3正常保护作用的基础， 心血管疾病，关注血液和脉管系统中生物活性LPA的来源。在 初步研究发现，LPA的循环水平对小鼠和人类的饮食非常敏感。这 LPA的饮食敏感池主要与肠内形成的致动脉粥样硬化脂蛋白有关 来自膳食脂肪和脂质（乳糜细胞及其残余物）或在肝脏中产生（低密度 脂蛋白）。血浆中的LPA可以通过自分泌运动因子（ATX）由溶血甘油磷脂制成， 分泌溶血磷脂酶D酶支持的假设，外源性和内源性来源的 循环LPA来自肠或肝中形成的溶血磷脂。LPA也是一个 甘油三酯是肠和肝脏合成甘油三酯的中间体，因此，由于该过程与 在这些致动脉粥样硬化脂蛋白的产生之后，血浆LPA也可能重新产生。第一 这项建议的目的是通过使用稳定同位素示踪剂和质量直接测试这些相互竞争的假设。 在小鼠和人类中进行的光谱分析研究，以直接鉴定循环LPA的前体。项小鼠研究 将使我们能够使用遗传和药理学方法来选择性地操纵ATX，LPP 3和 肠和肝源性脂蛋白的形成和清除。致动脉粥样硬化脂蛋白引发信号传导 血液和血管细胞类型的反应，是心血管疾病发生和发展的基础。 通过促进血管内皮的渗透性、表型调节和增殖/迁移而引起的疾病 血管平滑肌细胞和经典的巨噬细胞泡沫细胞反应。第二个目标 该提案将测试这些脂蛋白的LPA含量是这些反应的决定因素的假设。 LPA存在于动脉粥样硬化血管中，并且LPA的释放可能有助于血小板活化， 斑块破裂期间血栓形成。本提案的最终目的是使用最先进的质谱法 基于成像来检验动脉粥样硬化相关的LPA作为以下结果进行性累积的假设： 在动脉粥样硬化的发展过程中脂蛋白外渗。总之，这些研究将建立在 在本资助期内完成的研究，提供了有关 饮食对生物活性脂质信号通路的影响，该通路与遗传性心血管疾病密切相关 疾病风险。这项研究可以为通过饮食减少心血管疾病风险的策略提供信息。 降低致动脉粥样硬化脂蛋白相关LPA的干预措施，并将进一步强调 药理学靶向LPA代谢和信号传导以减轻心血管疾病风险。

Veterans have a higher incidence of cardiovascular disease than the general population. Cardiovascular disease risk is caused by environmental and heritable factors. The broad goal of our research is to understand how these factors interact to determine overall disease risk. In current funding period of this award we studied how heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3) associate with heritable coronary artery disease risk. We showed that disease risk associated loci within the final intron of the gene decrease expression of the gene in blood and vascular cells and that PLPP3 deficiency in mice results in accelerated atherosclerosis. Our findings support the concept that PLPP3 functions as an “atherosclerosis suppressor” gene and that heritable variants that decrease expression of the gene promote heart disease risk. LPP3 is an integral membrane cell surface enzyme that can dephosphorylate and inactivate bioactive lipid mediators. One of these LPP3 substrates, lysophosphatidic acid (LPA) acts on multiple blood and vascular cells to promote inflammation and cardiovascular disease progression. In mice, genetic or pharmacological targeting of LPA modulates atherosclerosis. In our mouse studies, LPP3 deficiency was associated with increased levels of LPA in the blood and vascular tissues. These results support our overarching hypothesis that dephosphorylation and inactivation of LPA underlies the normally protective effect of LPP3 on cardiovascular disease focusing attention on the sources of bioactive LPA in the blood and vasculature. In preliminary studies we found that circulating levels of LPA are very sensitive to diet in mice and humans. This diet sensitive pool of LPA is largely associated with atherogenic lipoproteins that are formed in the intestine from dietary fats and lipids (chylomocrons and their remnants) or are made in the liver (low density lipoproteins). LPA in blood plasma can be made from lysoglycerophospholipids by autotaxin (ATX) which is a secreted lysophospholipase D enzyme supporting the hypothesis that exogenous and endogenous sources of circulating LPA come from lysophospholipids that are formed in the intestine or the liver. LPA is also an intermediate in the synthesis of triglycerides by the intestine and liver so, since this process is coupled to the generation of these atherogenic lipoproteins it is also possible that plasma LPA is generated de novo. The first aim of this proposal will test these competing hypotheses directly by using stable isotope tracers and mass spectrometry studies in mice and humans to directly identify precursors of circulating LPA. The mouse studies will allow us to use genetic and pharmacological approaches to selectively manipulate ATX, LPP3 and the formation and clearance of intestinal and hepatic derived lipoproteins. Atherogenic lipoproteins elicit signaling responses in blood and vascular cell types that underlie the initiation and progression of cardiovascular disease by promoting permeability of vascular endothelium, phenotypic modulation and proliferation/migration of vascular smooth muscle cells and the classical macrophage foam cell response. The second aim of the proposal will test the hypothesis that the LPA content of these lipoproteins is a determinant of these responses. LPA is present in atherosclerotic blood vessels and release of LPA may contribute to platelet activation and thrombosis during plaque rupture. The final aim of this proposal will use state of the art mass spectrometry based imaging to test the hypothesis that atheroma associated LPA accumulates progressively as a result of lipoprotein extravasation during the development of atherosclerosis. Together, these studies will build on the research accomplished during the present funding period by providing important new information about the impact of diet on a bioactive lipid signaling pathway that is now strongly implicated in heritable cardiovascular disease risk. This research could inform strategies to mitigate cardiovascular disease risk through dietary interventions that decrease atherogenic lipoprotein associated LPA and will further underscore the value of pharmacological targeting of LPA metabolism and signaling to mitigate cardiovascular disease risk.