Lysophosphatidic acid and cardiovascular disease risk

退伍军人心血管疾病的发病率高于普通人群。心血管病 疾病风险是由环境和遗传因素引起的。我们研究的广泛目标是了解 这些因素如何相互作用来确定总体疾病风险。在本奖项的当前资助期内，我们研究了 编码脂质磷酸酶3(LPP3)的PLPP3基因的可遗传变异与 可遗传的冠状动脉疾病风险。我们发现与疾病风险相关的基因座在基因的最终内含子 PLPP3基因在小鼠血液和血管细胞中表达降低及PLPP3缺陷导致 加速动脉粥样硬化。我们的研究结果支持PLPP3作为动脉粥样硬化的功能的概念 抑制者“基因和降低该基因表达的可遗传变异会增加心脏病的风险。 LPP3是一种完整的膜细胞表面酶，具有去磷酸化和钝化生物活性脂质的功能 调解人。溶血磷脂酸(LPA)是这些LPP3底物之一，作用于多种血液和血管 促进炎症和心血管疾病进展的细胞。在小鼠身上，遗传或药理学 靶向LPA调节动脉粥样硬化。在我们的小鼠研究中，LPP3缺乏与 血液和血管组织中LPA水平升高。这些结果支持我们的总体假设。 LPA的去磷酸化和失活是LPP3正常保护作用的基础 心血管疾病关注血液和血管系统中具有生物活性的LPA的来源。在……里面 初步研究发现，在老鼠和人类中，循环中的LPA水平对饮食非常敏感。这 LPA的饮食敏感池在很大程度上与肠道中形成的致动脉粥样硬化脂蛋白有关 从膳食脂肪和类脂(乳杆菌及其残留物)或在肝脏(低密度)中产生 脂蛋白)。血浆中的LPA可由溶酶甘油磷脂通过自体趋化蛋白(ATX)生成，ATX是一种 分泌型溶血磷脂酶D酶支持外源性和内源性来源 循环中的LPA来自于肠道或肝脏中形成的溶血磷脂。LPA也是一种 肠道和肝脏合成甘油三酯的中间体，由于这一过程与 这些致动脉粥样硬化脂蛋白的产生也有可能是血浆LPA从头产生。第一 这项提议的目的是通过使用稳定的同位素示踪剂和质量来直接检验这些相互竞争的假说 在小鼠和人类中进行的光谱研究，以直接识别循环中LPA的前体。小鼠的研究 将允许我们使用遗传和药理学方法选择性地操纵ATX、LPP3和 肠源性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转导 心血管疾病发生和发展过程中血液和血管细胞类型的反应 通过促进血管内皮细胞通透性、表型改变和增殖/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。的第二个目标 该提案将检验这一假设，即这些脂蛋白的LPA含量是这些反应的决定因素。 LPA存在于动脉粥样硬化的血管中，LPA的释放可能有助于血小板的激活和 斑块破裂时血栓形成。这项提案的最终目标将使用最先进的质谱学 基于成像来检验动脉粥样硬化相关LPA逐渐累积的假说 动脉粥样硬化发展过程中的脂蛋白外溢。总之，这些研究将建立在 在本供资期间完成的研究，提供了关于 饮食对生物活性脂质信号通路的影响，该信号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参考 降低导致动脉粥样硬化的脂蛋白相关的LPA的干预措施，并将进一步强调 LPA代谢的药理学靶向和减轻心血管疾病风险的信号传递。

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.