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：
8116670
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 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116670
关键词：
Acute myocardial infarction Air Air Pollutants Air Pollution Animal Model Antibodies Aorta ApoE knockout mouse Apolipoproteins Arterial Fatty Streak Atherosclerosis Automobile Exhaust Biological Markers Blood - brain barrier anatomy Blood Vessels Brain Breathing Cardiovascular Diseases Cardiovascular system Caring 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 Health Histocytochemistry Human Immunofluorescence Immunologic In Situ Inflammatory Ischemic Stroke Knockout Mice LOX gene Lectin Lipoproteins Low Density Lipoprotein Receptor Low-Density Lipoproteins MAPK11 gene MAPK3 gene MAPK8 gene MMP9 gene Matrix Metalloproteinases Mediating Mediator of activation protein Mitogen-Activated Protein Kinase 3 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

Acute myocardial infarction Air Air Pollutants Air Pollution Animal Model Antibodies Aorta ApoE knockout mouse Apolipoproteins Arterial Fatty Streak Atherosclerosis Automobile Exhaust Biological Markers Blood - brain barrier anatomy Blood Vessels Brain Breathing Cardiovascular Diseases Cardiovascular system Caring 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 Health Histocytochemistry Human Immunofluorescence Immunologic In Situ Inflammatory Ischemic Stroke Knockout Mice LOX gene Lectin Lipoproteins Low Density Lipoprotein Receptor Low-Density Lipoproteins MAPK11 gene MAPK3 gene MAPK8 gene MMP9 gene Matrix Metalloproteinases Mediating Mediator of activation protein Mitogen-Activated Protein Kinase 3 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

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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事件发生率的增加有关，但是涉及的细胞途径尚未阐明。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。我们报道了与车辆排气相关的升高血管MMP-9，但是在该模型中MMP-9的调节尚未阐明。该提议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，车辆工程排放（VEE），导致氧化脂蛋白（OXLDL）介导的内皮素-1（1）（ET-1）诱导的诱导，并通过eTa Intaine（Et-eta Mistication）（ETA-ETA ICTICTAINT（ETA）激活MMP-9，并激活了MMP-9的激活（对于提出的实验，我们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，我们将研究参与ET-1介导的血管MMP-9表达的IHE分子途径，并分别通过使用ET-1受体拮抗剂（BQ-123）和MMP Inibibitor，调节MMP组织抑制剂（TIMP）（TIMP）。将分析产生的MAPK途径ERK1/2，P38和JNK表达。在AIM 2中，我们将Wili Detennine通过BQ-123处理在冠状动脉和脑上骨管系统中是否导致ET-1和MMP-9升高。将分析MMP-9和TIMP表达以及细胞定位。在AIM 3中，我们。将通过抗LOX-1抗体表达敲低的ET-1和MMP9来阐明通过凝集素样OxLdL受体（LOX-1）在调节诱导中的OXLDL信号传导在调节诱导中的作用。 MMP-S和可溶性LOX-1，在鼠和人类样品中。：