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：
7923996
负责人：
Amie Kathleen Lund
金额：
$ 24.9万
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：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7923996
关键词：
Acute myocardial infarction Air Air Pollutants Air Pollution Animal Model Antibodies Aorta ApoE knockout mouse Apolipoprotein E Apolipoproteins Arterial Fatty Streak Atherosclerosis Automobile Exhaust Biological Markers 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 EUK-189 Endopeptidases Endothelin A Receptor Endothelin-1 Environmental Air Pollutants Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Epidemiology Event Exposure to Extracellular Matrix Family Functional disorder Future Gasoline Gelatinase B Genetic Transcription Goals Growth Healthcare Histocytochemistry Human Immunofluorescence Immunologic In Situ Inflammatory Ischemic Stroke LDL-Receptor Related Protein 1 Lectin Lipoproteins Low Density Lipoprotein Receptor Low-Density Lipoproteins MAPK11 gene MAPK8 gene MMP9 gene Matrix Metalloproteinases Mediating Mediator of activation protein Messenger RNA Mitogen-Activated Protein Kinases Modeling Molecular Morbidity - disease rate Mus Myocardial Infarction Outcome Particulate Pathogenesis Pathology Pathway interactions Phase Plasma Production Proteins Rattus Reactive Oxygen Species Regulation Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Rupture Sampling Signal Pathway Signal Transduction Stroke Testing Time Tissue Inhibitor of Metalloproteinase-1 Tissue Inhibitor of Metalloproteinases Tissues United States Vascular remodeling Western Blotting arterial lesion arterial remodeling base cerebrovascular improved inhibitor/antagonist mRNA Expression member mortality neutralizing antibody oxidized LDL receptors oxidized low density lipoprotein protein expression receptor research study response

项目摘要

Atherosclerosis, an Inflamniatory 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 incidents, however the cellular pathways involved have not yet been elucidated. Remodeling of arterial extracellular matrix (ECM) is a crucial step in the progression of atherosclerosis, which is primarily regulated through matrix metalloproteinase (MMP) activity. We have reported elevated vascular MMP-9 associated with inhaiational exposure to vehicular 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, vehicular engiiie emissions (VEE), 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, we will utilize atherosclerosis-prone ApoE knockout mice. In Aim 1, we will investigate Ihe molecular pathways involved in ET-1-mediated expression of vascular MMP-9, and regulation of MMP tissue inhibitors (TIMPs), following exposure to VEE, through use of an ET-1 receptor antagonist (BQ-123) and a MMP inihibitor, respectively. Resulting MAPK pathway ERK1/2, p38, and JNK expression will be analyzed. In Aim 2, we wili detennine whether VEE results in elevated ET-1 and 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, we. 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 VEE by anti-LOX-1 antibody expression knockdown^ In Aim 4, we will deterrnine whether exposure to common environmental air pollutants (VEE,: mixed gasolinerand diesel exhaust) results in expression of circulating biomarkers, MMP-S and soluble LOX-1, in murine and-human samples. :

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事件发生率增加有关，但所涉及的细胞途径尚未阐明。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。我们报道了血管 MMP-9 升高与吸入性暴露于汽车尾气相关，但该模型中 MMP-9 的调节尚未阐明。该提案的目的是检验以下假设：暴露于普遍存在的环境空气污染物、车辆发动机排放物 (VEE) 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系统的激活。通过 ET-1 - ETA 丝裂原激活蛋白激酶 (MAPK) 信号通路循环 MMP-9。对于所提出的实验，我们将利用易发生动脉粥样硬化的 ApoE 基因敲除小鼠。在目标 1 中，我们将通过使用 ET-1 受体拮抗剂 (BQ)，研究暴露于 VEE 后参与 ET-1 介导的血管 MMP-9 表达以及 MMP 组织抑制剂 (TIMP) 调节的分子途径。 -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，我们将确定 BQ-123 治疗时 VEE 是否会导致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，我们。将阐明 oxLDL 信号传导通过凝集素样 oxLDL 受体 (LOX-1) 在调节 ET-1 和 MMP9 诱导中的作用，通过抗 LOX-1 抗体表达敲低来响应暴露于 VEE^ 在目标 4 中，我们将确定暴露于常见环境空气污染物（VEE，：混合汽油和柴油废气）是否会导致循环生物标志物 MMP-S 和可溶性物质的表达LOX-1，存在于小鼠和人类样本中。：