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

• 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
• 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

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性疾病，是全球发病率和死亡率的主要原因。 斑块破裂通常导致临床结局，如中风或急性心肌梗死（AMI）。 大量流行病学证据表明，颗粒和气体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，其主要通过基质金属蛋白酶（MMP）活性调节。 研究者已经报道了与吸入暴露于汽油废气相关的血管MMP-9升高;然而，该模型中MMP-9的调节尚未阐明。 本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物（GEE）导致氧化脂蛋白（oxLDL）介导的内皮素-1（ET-1）诱导以及通过ET-1 - ETA丝裂原活化蛋白激酶（MAPK）信号通路激活血管和循环MMP-9。 对于拟议的实验，研究人员将利用动脉粥样硬化倾向的ApoE基因敲除小鼠。 在目标1中，他们将分别通过使用ET-1受体拮抗剂（BQ-123）和MMP抑制剂，研究暴露于GEE后，ET-1介导的血管MMP-9表达和MMP组织抑制剂（TIMP）调节的分子途径。 将分析所得MAPK途径ERK 1/2、p38和JNK表达。 在目标2中，他们将确定GEE是否导致BQ-123治疗的冠状动脉和血管系统中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，研究人员将阐明oxLDL信号转导的作用，通过凝集素样oxLDL受体（LOX-1），在调节ET-1和MMP 9的诱导，响应于暴露于GEE的抗LOX-1抗体表达敲低。 在目标4中，他们将确定暴露于常见的环境空气污染物（GEE，柴油机废气，木材烟雾）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的巨大负担，识别参与此类疾病的起始和/或进展的环境因素和分子途径至关重要，这些因素和分子途径可作为治疗的靶点。