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有关的炎症性疾病，是全球发病率和死亡率的主要原因。斑块破裂通常会导致临床结果，例如中风或急性心肌梗塞（AMI）。大量的流行病学证据表明，颗粒和气态空气污染物与心血管发病率的增加有关。但是，所涉及的细胞途径尚不清楚。动脉外基质（ECM）的重塑是动脉粥样硬化进展的关键步骤，该步骤主要通过基质金属蛋白酶（MMP）活性调节。研究人员报告说，与汽油排气的吸入暴露有关的血管MMP-9升高。但是，在此模型中MMP-9的调节尚未阐明。该提案的目的是检验以下假设：暴露于无处不在的环境空气污染物，汽油发动机排放（GEE），导致氧化脂蛋白（OXLDL）介导的内皮蛋白-1（ET-1）诱导血管和循环MMP-9通过ETA-1-ETA-ETA-ETA MITOGEN蛋白酶蛋白酶蛋白（ETA-ETA）诱导的诱导和循环的MMP-9激活。对于提出的实验，研究人员将利用容易发生动脉粥样硬化的APOE基因敲除小鼠。在AIM 1中，他们将研究与ET-1介导的血管MMP-9表达所涉及的分子途径，并分别通过使用ET-1受体拮抗剂（BQ-123）和MMP抑制剂来调节MMP组织抑制剂（TIMP）（TIMP）（TIMP）。将分析产生的MAPK途径ERK1/2，P38和JNK表达。在AIM 2中，他们将确定GEE是否会在冠状动脉和脑血管形系统中升高ET-1和MMP-9。将分析MMP-9和TIMP表达以及细胞定位。在AIM 3中，研究者将通过凝集素样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，以响应抗LOX-1抗体表达敲低对GEE的暴露。在AIM 4中，他们将确定在鼠和人类样品中暴露于常见的环境空气污染物（GEE，柴油排气，木材的木材）是否会导致循环生物标志物，MMP-9和可溶性LOX-1的表达。相关性：考虑到当今医疗保健的动脉粥样硬化，AMI和中风的压倒性负担，确定这种疾病起始和/或进展的环境因素和分子途径至关重要，这可能是治疗的靶标。