Air Pollution-Induced Vascular Endothelin Regulation of MMP Activity.

空气污染诱导的血管内皮素对 MMP 活性的调节。

• 批准号: 7222181
• 负责人: Amie Kathleen Lund
• 金额: $ 4.6万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7222181
• 关键词: air pollution; atherosclerosis; cardiovascular disorder epidemiology; cellular pathology; disease /disorder model; endothelin; engine exhaust; environmental exposure; enzyme activity; enzyme induction /repression; extracellular matrix; free radical oxygen; gene expression; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; metalloendopeptidases; pathologic process; petroleum oil; polymerase chain reaction; postdoctoral investigator; vascular endothelium

DESCRIPTION (provided by applicant): Atherosclerosis, an inflammatory disease associated with the production and degradation of the extracellular matrix (ECM) and accumulation of lipids in the arterial wall, is the leading cause of morbidity and mortality worldwide. Substantial epidemiological evidence indicates that particulate and gaseous air pollutants are associated with adverse human health effects, specifically increased rates of cardiovascular incidents. However, the mechanistic cellular and molecular pathways involved in the effects of inhaled environmental air pollutants on the progression of cardiovascular disease have not yet been elucidated. Remodeling of arterial ECM is a crucial step in the progression of atherosclerosis, which is thought to be primarily regulated through matrix metalloproteinase (MMP) expression and activity. However, it has not yet been determined whether MMP activity is involved in the progression of atherosclerosis in association with exposure to common environmental air pollutants. The goal of this proposal is to test the hypothesis that chronic exposure to environmental air pollutants, specifically gasoline engine emissions, results in upregulation of reactive oxygen species (ROS) and subsequent induction of molecular pathways involved in the progression of atherosclerosis. For the purpose of the experiments proposed, herein, we will utilize the animal model of atherosclerosis-prone ApoE knockout mice. In Aim 1, it will be determined whether subchronic exposure to gasoline engine exhaust results in upregulation and subsequent activation of the MMP pathway.which is associatiated with the progression of atherosclerosis. To do this, we will look at the expression and activity of specific members of the MMP proteinase family that have previously been found to be upregulated in the pathogenesis and progression of atherosclerosis. In Aim 2, we will attempt to identify which pathways are involved in induction of MMPs. Specifically we will target the production of ROS, and vasoactive peptide endothelin-1 (ET-1). Additionally, we will determine whether ET-1 expression is being mediated through a ROS (via antioxidant therapy) pathway in atherosclerotic vessels exposed to gasoline engine emission. Finally, in Aim 3, it will be determined whether ET-1 is directly regulating MMP expression and activation by utilizing an ET-1 receptor antagonist therapy in conjunction with the exposures. Considering the ramifications of cardiovascular disease diagnosis and treatment on health care today, it is critical to determine which factors may contribute to the onset and/or progression of such diseases. Identification of environmental factors, and the cellular pathways they potentate, associated with cardiovascular disease progression is critical for both prevention and pharmacological therapy.

描述（由申请人提供）：动脉粥样硬化，一种与细胞外基质（ECM）的产生和降解相关的炎性疾病（ECM）以及脂质在动脉壁中的积累，是全球发病率和死亡率的主要原因。大量的流行病学证据表明，颗粒和气态空气污染物与不良人类健康效应有关，特别是增加心血管事件的率。然而，尚未阐明吸入环境空气污染物对心血管疾病进展的影响的机械细胞和分子途径。动脉ECM的重塑是动脉粥样硬化进展的关键步骤，被认为主要是通过基质金属蛋白酶（MMP）表达和活性调节的。但是，尚未确定MMP活性是否与暴露于常见环境空气污染物有关的动脉粥样硬化进展。该提案的目的是检验以下假设：长期暴露于环境空气污染物，特别是汽油发动机排放，导致活性氧（ROS）的上调以及随后诱导参与动脉粥样硬化进展的分子途径。出于提出的实验目的，我们将利用容易发生动脉粥样硬化的APOE基因敲除小鼠的动物模型。在AIM 1中，将确定在汽油发动机排气中的亚慢性暴露是否会导致MMP途径的上调和随后的激活。哪个与动脉粥样硬化的进展相关。为此，我们将研究MMP蛋白酶家族的特定成员的表达和活性，这些成员以前被发现在动脉粥样硬化的发病机理和进展中被上调。在AIM 2中，我们将尝试确定与MMP诱导有关的途径。具体而言，我们将针对ROS的产生，以及血管活性肽内皮素-1（ET-1）。此外，我们将确定是否通过暴露于汽油发动机发射的动脉粥样硬化血管中的ROS（通过抗氧化剂治疗）途径介导ET-1表达。最后，在AIM 3中，将确定ET-1是否通过利用ET-1受体拮抗剂治疗与暴露来直接调节MMP表达和激活。考虑到当今医疗保健对心血管疾病诊断和治疗的影响，确定哪些因素可能有助于这种疾病的发作和/或进展。与心血管疾病进展相关的环境因素及其预防的细胞途径的鉴定对于预防和药理治疗至关重要。