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）：动脉粥样硬化是一种与细胞外基质（ECM）的产生和降解以及动脉壁脂质积聚相关的炎症性疾病，是全世界发病和死亡的主要原因。大量流行病学证据表明，颗粒物和气态空气污染物与人类健康的不良影响有关，特别是增加心血管事件的发生率。然而，吸入环境空气污染物对心血管疾病进展影响的机制细胞和分子途径尚未阐明。动脉 ECM 重塑是动脉粥样硬化进展的关键步骤，被认为主要通过基质金属蛋白酶 (MMP) 表达和活性进行调节。然而，尚未确定 MMP 活性是否与暴露于常见环境空气污染物相关的动脉粥样硬化进展有关。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物，会导致活性氧（ROS）上调，并随后诱导参与动脉粥样硬化进展的分子途径。为了本文提出的实验的目的，我们将利用易发生动脉粥样硬化的 ApoE 敲除小鼠的动物模型。在目标 1 中，将确定亚慢性暴露于汽油发动机废气是否会导致 MMP 途径的上调和随后的激活，这与动脉粥样硬化的进展相关。为此，我们将研究之前发现在动脉粥样硬化的发病机制和进展中上调的 MMP 蛋白酶家族特定成员的表达和活性。在目标 2 中，我们将尝试确定哪些途径参与 MMP 的诱导。具体来说，我们将针对 ROS 和血管活性肽内皮素-1 (ET-1) 的产生。此外，我们将确定暴露于汽油发动机排放物的动脉粥样硬化血管中 ET-1 表达是否是通过 ROS（通过抗氧化治疗）途径介导的。最后，在目标 3 中，将通过结合暴露使用 ET-1 受体拮抗剂疗法来确定 ET-1 是否直接调节 MMP 表达和激活。考虑到心血管疾病诊断和治疗对当今医疗保健的影响，确定哪些因素可能导致此类疾病的发作和/或进展至关重要。识别与心血管疾病进展相关的环境因素及其增强的细胞途径对于预防和药物治疗至关重要。