Lysophosphatidic acid and cardiovascular disease risk

溶血磷脂酸与心血管疾病风险

• 批准号: 9858243
• 负责人: ANDREW J MORRIS
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9858243
• 关键词: Adipose tissue; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Attention; Award; Biological Markers; Blood; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Caring; Cell membrane; Cell surface; Cells; Cholesterol; Chylomicrons; Coronary Arteriosclerosis; Coronary artery; Coupled; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Dietary Fats; Dietary Intervention; Dietary Phospholipid; Disease; Disease Progression; Endothelium; Enterocytes; Environmental Risk Factor; Enzymes; Extravasation; Family; Fasting; Fatty acid glycerol esters; Foam Cells; Funding; Gene Expression; General Population; Generations; Genes; Genetic; Goals; Heart; Heart Diseases; Hepatic; Heritability; Human; Image; In Vitro; Incidence; Individual; Inflammation; Ingestion; Inherited; Intestines; Introns; Investigation; Lead; Life Style; Link; Lipids; Lipoproteins; Liver; Low-Density Lipoproteins; Lysophospholipase; Lysophospholipids; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metabolic; Metabolism; Methods; Mus; Myocardial Infarction; Myocardial Ischemia; Obesity; Overweight; Oxides; Pathologic; Permeability; Pharmacology; Phenotype; Phospholipids; Plasma; Platelet Activation; Prevention; Process; Protein Dephosphorylation; Recording of previous events; Research; Risk Factors; Rupture; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Suppressor Genes; Testing; Thrombosis; Tissues; Tracer; Triglycerides; Unhealthy Diet; United States; Variant; Vascular Smooth Muscle; Very low density lipoprotein; Veterans; Weight maintenance regimen; Woman; base; cardiovascular disorder risk; cell motility; cell type; dietary; disorder risk; feeding; heart disease risk; insight; lipid mediator; lipid phosphate phosphatase; lysophosphatidic acid; macrophage; men; monocyte; mortality; mouse model; novel therapeutics; nutrition; obese person; oxidized low density lipoprotein; particle; prevent; protective effect; recruit; response; stable isotope; vascular endothelium permeability; vascular inflammation; vascular smooth muscle cell migration

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.

退伍军人的心血管疾病患者比一般人群更高。 疾病风险是由环境和可遗传的因素引起的。我们研究的广泛目标是了解 这些因素如何相互作用以确定总体疾病风险。在本奖项的当前资助期间，我们研究了 编码脂质磷酸磷酸酶3（LPP3）的PLPP3基因的可遗传变体与 可遗传的冠状动脉疾病风险。我们表明，疾病风险与最终内含子内的基因座相关 基因降低了血液和血管细胞中基因的表达以及小鼠的PLPP3缺乏导致 加速动脉粥样硬化。我们的发现支持PLPP3作为“动脉粥样硬化的概念 抑制剂”基因和降低基因表达的可遗传变体促进心脏病风险。 LPP3是一种整体膜细胞表面酶，可以使生物活性脂质脱磷酸化和失活 调解人。这些LPP3底物之一，溶物磷脂酸（LPA）作用于多种血液和血管 细胞促进炎症和心血管疾病进展。在小鼠中，遗传学或药理 LPA的靶向调节动脉粥样硬化。在我们的小鼠研究中，LPP3缺乏症与 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的去磷酸化和灭活是LPP3通常受保护的作用 心血管疾病将注意力集中在血液和脉管系统中的生物活性LPA来源上。在 初步研究我们发现，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中形成的动脉粥样硬化脂蛋白有关 从饮食中的脂肪和脂质（乳糜隆及其残留物）中或在肝脏中制成（低密度 脂蛋白）。血浆中的LPA可以由Autotaxin（ATX）用溶血甘油磷脂制成 分泌的溶血脂蛋白酶D酶支持了外源和内源性来源的假设 循环LPA来自肠道或肝脏中形成的溶物磷脂。 LPA也是 肠道和肝脏合成甘油三酸酯的中间体，因为此过程耦合到 这些动脉粥样硬化脂蛋白的产生也可能是从头产生的。第一个 该提案的目的将通过使用稳定的同位素示踪剂和质量直接检验这些竞争假设 在小鼠和人类中的光谱研究直接鉴定循环LPA的前体。小鼠研究 将允许我们使用遗传和药物方法选择性操纵ATX，LPP3和 肠炎和肝炎衍生的脂蛋白的形成和清除。动脉粥样硬化脂蛋白引起信号传导 血液和血管细胞类型的反应是心血管主动性和进展的基础 通过促进血管内皮的渗透性，表型调节和增殖/迁移 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 提案将检验以下假设：这些脂蛋白的LPA含量是这些反应的确定。 LPA存在于动脉粥样硬化血管中，LPA的释放可能有助于血小板激活和 斑块破裂期间的血栓形成。该提案的最终目的将使用最先进的质谱法 基于成像以检验有关牵化性LPA的假设，逐渐积累 动脉粥样硬化过程中脂蛋白渗出。这些研究将共同​​基于 通过提供有关有关的重要新信息，在当前资助期间完成的研究 饮食对生物活性脂质信号传导途径的影响，该途径现在与遗传性心血管息息相关 疾病风险。这项研究可以为减轻心血管疾病风险的策略提供信息 减少动脉粥样硬化脂蛋白相关的LPA的干预措施，并将进一步强调 LPA代谢和信号传导的药理靶向减轻心血管疾病风险。