Air Pollution-Induced Vascular Endothelin Regulation of MMP Activity.

描述(申请人提供)：动脉粥样硬化是一种炎症性疾病，与细胞外基质(ECM)的产生和降解以及脂质在动脉壁中的积聚有关，是全球发病率和死亡率的主要原因。大量流行病学证据表明，空气中的颗粒物和气态污染物会对人类健康造成不利影响，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的影响所涉及的细胞和分子机制尚未阐明。动脉ECM重塑是动脉粥样硬化进展过程中的关键步骤，目前认为其主要受基质金属蛋白酶(MMPs)表达和活性调节。然而，目前还没有确定基质金属蛋白酶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的进展有关。这项建议的目的是检验一种假设，即长期暴露于环境空气污染物，特别是汽油发动机排放，会导致活性氧物种(ROS)上调，并随后诱导参与动脉粥样硬化进展的分子途径。为了实验的目的，在这里，我们将利用易患动脉粥样硬化的载脂蛋白E基因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尾气是否会导致基质金属蛋白酶途径的上调和随后的激活，这与动脉粥样硬化的进展有关。为此，我们将研究之前发现在动脉粥样硬化的发生和发展中上调的特定的基质金属蛋白酶家族成员的表达和活性。在目标2中，我们将尝试确定哪些途径参与了MMPs的诱导。具体来说，我们将针对ROS和血管活性多肽ET-1(ET-1)的产生。此外，我们将确定ET-1的表达是否通过ROS(通过抗氧化治疗)途径在暴露于汽油发动机排放的动脉粥样硬化血管中介导。最后，在目标3中，将确定ET-1是否通过结合使用ET-1受体拮抗剂治疗来直接调节基质金属蛋白酶的表达和激活。考虑到当今心血管疾病诊断和治疗对卫生保健的影响，确定哪些因素可能导致此类疾病的发生和/或发展是至关重要的。识别与心血管疾病进展相关的环境因素及其作用的细胞通路，对于预防和药物治疗都是至关重要的。

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.