Effect of Organophoshate Exposure on Cholesteryl Ester Hydrolase

有机磷酸盐暴露对胆固醇酯水解酶的影响

基本信息

批准号：
7811262
负责人：
MATTHEW K ROSS
金额：
$ 6.72万
依托单位：
MISSISSIPPI STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7811262
关键词：
2-arachidonylglycerol Aftercare Age Agonist Agriculture American Heart Association Animal Disease Models Area Arterial Fatty Streak Arteries Atherosclerosis Bile fluid Binding Biochemical Reaction Biochemistry CNR1 gene CNR2 gene Cannabinoids Carboxylic Ester Hydrolases Cardiology Cardiovascular Diseases Cause of Death Cell Culture System Cell Line Cell Proliferation Cells Chlorpyrifos Cholesterol Cholesterol Esters Cholesterol Homeostasis Chronic Combined Modality Therapy Complex Connective Tissue Coronary Arteriosclerosis Coronary artery Country Data Databases Development Disease Dose Endocannabinoids Environmental Health Environmental Risk Factor Enzymes Esters Exposure to Family Florida Foam Cells Functional disorder Funding G-Protein-Coupled Receptors Genbank Goals Grant Healed Health High Density Lipoproteins Human Hydrolysis Hypertension Immune Inflammation Mediators Inflammatory Insecticides Investigation Laboratories Ligands Lipid Binding Lipids Liver Low-Density Lipoproteins Marijuana Mediating Metabolism Methyl Parathion Mississippi Modeling Movement Neuraxis O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate Organophosphates PTGS2 gene Paraoxon Parathion Patients Peripheral Pesticides Pharmacological Treatment Phenotype Physiological Play Prevalence Process Prostaglandins Protein Isoforms Proteins Publishing Recombinants Recording of previous events Regulation Research Research Project Grants Risk Risk Factors Role Serine Serum Severities Smooth Muscle Myocytes Southeastern United States Stimulus Stroke Students System Testing Tissues Toxic Environmental Substances Training Transport Process United States United States National Institutes of Health Universities Work Xenobiotics adduct anandamide autocrine base cDNA Library cannabinoid receptor carboxylesterase environmental chemical environmental toxicology esterase extracellular healing human disease low socioeconomic status macrophage member monocyte mortality novel oxidized low density lipoprotein paracrine parent grant particle prevent progesterone 11-hemisuccinate-(2-iodohistamine)public health relevance receptor response reverse cholesterol transport statistics suicide inhibitor theories toxic organophosphate insecticide exposure toxicant uptake

项目摘要

DESCRIPTION (provided by applicant): The rate-limiting step in reverse cholesterol transport from macrophages is the hydrolysis of cholesteryl esters to free cholesterol, which is subsequently transported out of the cell to cholesterol acceptors. In human macrophages, the enzyme responsible for cholesteryl ester hydrolysis is carboxylesterase 1 (CES1). The overall hypothesis of parent grant R15 ES015348 was that exposure to bioactive metabolites of organophosphate (OP) insecticides will inhibit the ability of CES1 to hydrolyze cholesteryl esters, thus slowing the reverse cholesterol transport process and increasing the risk of atherosclerosis. Our published data, obtained during the current funding cycle, shows that CES1 can be inhibited by treatment with paraoxon, the active metabolite of the OP insecticide parathion, and that this inhibition can cause augmented accumulation of cholesteryl esters in human THP-1 macrophages (Crow et al., 2008). Moreover, our recent preliminary data show that recombinant CES1 and CES2 can hydrolyze the endocannabinoid compound 2-arachidonoylglycerol (2-AG) and its COX-2 derived prostaglandin-like metabolites (termed prostaglandin glyceryl esters or PG-Gs). Pretreatment of human THP-1 monocytes and macrophages with paraoxon can block the subsequent degradation of exogenously added 2-AG and PG-Gs. These are novel findings that suggest that exposure of CES1- and/or CES2-expressing cells to bioactive OP metabolites (e.g., paraoxon) will perturb the endocannabinoid tone in tissues composed of these cells. It has become increasingly clear that endogenous cannabinoids, which bind to the same class of receptors as the psychoactive component of marijuana (?9-THC), have important functions in health and disease. Therefore, we hypothesize that the endocannabinoid tone of vessel wall macrophages will be significantly perturbed by chronic exposure to bioactive OP metabolites and an activated endocannabinoid system can modulate cholesterol metabolism in macrophages. To explore this possibility, we propose to extend the scope of R15 ES015348 by studying the endocannabinoid system in a model cell culture system (macrophage foam cells) that we already use in the parent grant. To test our hypothesis we propose two aims: (1) Determine if combined treatment of cultured human THP-1 macrophages with oxidized (ox)LDL and bioactive metabolites of OP pesticides modulate components of the endocannabinoid system, including cannabinoid (CB) receptor levels, endocannabinoid biosynthetic enzymes, endocannabinoid catabolic enzymes (MAGL and CES1), and the levels of endocannabinoids themselves (2-AG and AEA). (2) Determine if endocannabinoids (2-AG and AEA) modulate cholesterol metabolism and efflux from human macrophages via a CB1- or CB2-mediated mechanism. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the number one killer in the United States. The underlying pathophysiology of atherosclerosis is complex and multifactorial. One critical factor in the development/progression of atherosclerosis is environmental factors, such as toxicants, that may accelerate disease. Our research seeks to examine whether organophosphate (OP) pesticides are etiologically associated with atherosclerosis. Our research indicates that there are enzymes that regulate cholesterol metabolism, which can be inhibited by bioactive metabolites of OP pesticides. This competitive supplement will allow us to study these mechanisms in greater detail.

描述（由申请人提供）：巨噬细胞反向胆固醇转运的限速步骤是胆固醇酯水解为游离胆固醇，随后将其转运出细胞至胆固醇受体。在人类巨噬细胞中，负责水解胆固醇酯的酶是羧酸酯酶 1 (CES1)。母基金 R15 ES015348 的总体假设是，接触有机磷酸酯 (OP) 杀虫剂的生物活性代谢物会抑制 CES1 水解胆固醇酯的能力，从而减慢胆固醇的反向转运过程并增加动脉粥样硬化的风险。我们在当前资助周期内获得的公布数据表明，CES1 可以通过对氧磷（OP 杀虫剂对硫磷的活性代谢物）治疗来抑制，并且这种抑制作用可以导致人 THP-1 巨噬细胞中胆固醇酯的积累增加（Crow等人，2008）。此外，我们最近的初步数据表明，重组CES1和CES2可以水解内源性大麻素化合物2-花生四烯酰甘油（2-AG）及其COX-2衍生的前列腺素样代谢物（称为前列腺素甘油酯或PG-G）。用对氧磷预处理人THP-1单核细胞和巨噬细胞可以阻止外源添加的2-AG和PG-G随后的降解。这些新发现表明，表达 CES1 和/或 CES2 的细胞暴露于生物活性 OP 代谢物（例如对氧磷）会扰乱由这些细胞组成的组织中的内源性大麻素张力。人们越来越清楚，内源性大麻素与大麻的精神活性成分 (?9-THC) 结合到同一类受体上，在健康和疾病中具有重要功能。因此，我们假设血管壁巨噬细胞的内源性大麻素基调会因长期接触生物活性OP代谢物而受到显着干扰，并且激活的内源性大麻素系统可以调节巨噬细胞中的胆固醇代谢。为了探索这种可能性，我们建议通过研究我们已在母基金中使用的模型细胞培养系统（巨噬细胞泡沫细胞）中的内源性大麻素系统来扩展 R15 ES015348 的范围。为了检验我们的假设，我们提出了两个目标：(1) 确定培养的人类 THP-1 巨噬细胞与氧化 (ox)LDL 和 OP 农药的生物活性代谢物联合治疗是否会调节内源性大麻素系统的组成部分，包括大麻素 (CB) 受体水平，内源性大麻素生物合成酶、内源性大麻素分解代谢酶（MAGL 和 CES1）以及内源性大麻素本身的水平（2-AG 和原子能机构）。 (2) 确定内源性大麻素（2-AG 和 AEA）是否通过 CB1 或 CB2 介导的机制调节胆固醇代谢和人巨噬细胞的流出。公共卫生相关性：动脉粥样硬化是美国的头号杀手。动脉粥样硬化的潜在病理生理学是复杂且多因素的。动脉粥样硬化发生/进展的关键因素之一是环境因素，例如可能加速疾病的有毒物质。我们的研究旨在探讨有机磷（OP）农药是否与动脉粥样硬化有病因学相关性。我们的研究表明，存在调节胆固醇代谢的酶，OP农药的生物活性代谢物可以抑制这种酶。这种竞争性补充将使我们能够更详细地研究这些机制。