MMP-9 Activity Mediates Vascular Effects of Inhaled Environmental Air Pollutants

MMP-9 活性介导吸入环境空气污染物的血管效应

基本信息

批准号：
7448763
负责人：
Amie Kathleen Lund
金额：
$ 9.38万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7448763
关键词：
Acute Acute myocardial infarction Air Pollutants Air Pollution Animal Model Antibodies ApoE knockout mouse Apolipoproteins Arterial Fatty Streak Atherosclerosis Attenuated BQ123 Biological Assay Biological Markers Blood Blood - brain barrier anatomy Blood Vessels Brain Breathing Cardiovascular Diseases Cardiovascular system Cause of Death Cessation of life Chronic Clinical Coronary Coronary artery Data Diesel Exhaust Disease Disruption Doxycycline End Point Endopeptidases Endothelin-1 Engine Exhaust Environmental Air Pollutants Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Etiology Event Exposure to Extracellular Matrix Extracellular Matrix Degradation Family Functional disorder Gasoline Gel Gelatinase B Genetic Transcription Goals Growth Healthcare Histocytochemistry Human Immunofluorescence Immunologic In Situ Incidence Individual Inflammatory Ischemic Stroke Knockout Mice Lectin Lipoproteins Localized Low Density Lipoprotein Receptor Low-Density Lipoproteins MAPK11 gene MAPK8 gene MMP9 gene Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mediating Mediator of activation protein Messenger RNA Mitogen-Activated Protein Kinases Modeling Molecular Morbidity - disease rate Mus Myocardial Infarction Outcome Ozone Particulate Pathogenesis Pathology Pathway interactions Physicians Plasma Polymerase Chain Reaction Process Production Proteins Rate Rattus Reactive Oxygen Species Regulation Reporting Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Rupture Sampling Signal Pathway Signal Transduction Smoke Source Stroke Superoxide Dismutase Testing Time Tissue Inhibitor of Metalloproteinase-1 Tissue Inhibitor of Metalloproteinases Tissues Today Translational Activation Vascular System Vascular remodeling Western Blotting Wood material arterial lesion arterial remodeling cerebrovascular circulating plasma factor day diagnosis evaluation exhaust inhibitor/antagonist mRNA Expression member mimetics mortality neutralizing antibody oxidized LDL receptors oxidized low density lipoprotein particle programs protein expression receptor research study response tempol

项目摘要

DESCRIPTION (provided by applicant) Atherosclerosis, an inflammatory disease associated with the production of arterial plaques, is the leading cause of morbidity and mortality worldwide. Plaque rupture commonly leads to clinical outcomes such as stroke or acute myocardial infarction (AMI). Substantial epidemiological evidence indicates that particulate and gaseous air pollutants are associated with increased rates of cardiovascular incidence; however the cellular pathways involved are unknown. Remodeling of arterial extracellular matrix (ECM) is a crucial step in the progression of atherosclerosis, which is primarily regulated through matrix metalloproteinase (MMP) activity. The investigators have reported elevated vascular MMP-9 associated with inhalational exposure to gasoline exhaust; however regulation of MMP-9 in this model has not been elucidated. The goal of this proposal is to test the hypothesis that exposure to the ubiquitous environmental air pollutant, gasoline engine emissions (GEE), results in oxidized lipoprotein (oxLDL)-mediated induction of endothelin-1 (ET-1) and activation of vascular and circulating MMP-9 through an ET-1 - ETA mitogen activated protein kinase (MAPK) signaling pathway. For the experiments proposed, the investigators will utilize atherosclerosis-prone ApoE knockout mice. In Aim 1, they will investigate the molecular pathways involved in ET-1-mediated expression of vascular MMP-9, and regulation of MMP tissue inhibitors (TIMPs), following exposure to GEE, through use of an ET-1receptor antagonist (BQ-123) and a MMP inhibitor, respectively. Resulting MAPK pathway ERK1/2, p38, and JNK expression will be analyzed. In Aim 2, they will determine whether GEE results in elevated ET-1and MMP-9 in the coronary and cerebrovasculature with BQ-123 treatment. MMP-9 and TIMP expression, and cellular localization will be analyzed. In Aim 3, the investigators will elucidate the role of oxLDL signaling, via lectin-like oxLDL receptor (LOX-1), in regulating induction of ET-1 and MMP9, in response to exposure to GEE by anti-LOX-1 antibody expression knockdown. In Aim 4, they will determine whether exposure to common environmental air pollutants (GEE, diesel exhaust, wood-smoke) results in expression of circulating biomarkers, MMP-9 and soluble LOX-1, in murine and human samples. Relevance: Considering the overwhelming burden of atherosclerosis, AMI, and stroke on healthcare today, it is critical to identify environmental factors and molecular pathways involved in the initiation and/or progression of such diseases, which may serve as targets for therapy.

描述（由申请人提供）动脉粥样硬化是一种与动脉斑块产生相关的炎症性疾病，是全世界发病和死亡的主要原因。斑块破裂通常会导致中风或急性心肌梗死 (AMI) 等临床结果。大量流行病学证据表明，颗粒物和气态空气污染物与心血管发病率增加有关；然而所涉及的细胞途径尚不清楚。动脉细胞外基质（ECM）的重塑是动脉粥样硬化进展的关键步骤，主要通过基质金属蛋白酶（MMP）活性进行调节。研究人员报告称，血管 MMP-9 升高与吸入汽油废气有关；然而，MMP-9 在该模型中的调节尚未阐明。该提案的目的是检验以下假设：暴露于普遍存在的环境空气污染物、汽油发动机排放物 (GEE) 会导致氧化脂蛋白 (oxLDL) 介导的内皮素-1 (ET-1) 诱导以及血管和神经细胞的激活。通过 ET-1 - ETA 丝裂原激活蛋白激酶 (MAPK) 信号通路循环 MMP-9。在拟议的实验中，研究人员将利用易患动脉粥样硬化的 ApoE 基因敲除小鼠。在目标 1 中，他们将通过使用 ET-1 受体拮抗剂（BQ- 123) 和 MMP 抑制剂。将分析由此产生的 MAPK 通路 ERK1/2、p38 和 JNK 表达。在目标 2 中，他们将确定 GEE 是否会导致 BQ-123 治疗后冠状动脉和脑血管系统中 ET-1 和 MMP-9 升高。将分析 MMP-9 和 TIMP 表达以及细胞定位。在目标 3 中，研究人员将通过抗 LOX-1 抗体表达响应 GEE 暴露，通过凝集素样 oxLDL 受体 (LOX-1) 阐明 oxLDL 信号传导在调节 ET-1 和 MMP9 诱导中的作用击倒。在目标 4 中，他们将确定暴露于常见环境空气污染物（GEE、柴油机尾气、木烟）是否会导致小鼠和人类样本中循环生物标志物 MMP-9 和可溶性 LOX-1 的表达。相关性：考虑到动脉粥样硬化、AMI 和中风对当今医疗保健造成的巨大负担，确定与此类疾病的发生和/或进展有关的环境因素和分子途径至关重要，它们可以作为治疗的目标。