ANGIOTENSIN II AND REGULATION OF MCP-1 GENE EXPRESSION

描述：(改编自应用程序)分子和细胞 高血压作为动脉粥样硬化的危险因素的潜在机制是 人们对此知之甚少。几条临床和实验证据 提示肾素-血管紧张素系统在促进 动脉粥样硬化的形成。单核细胞向血管壁的渗透是一个关键 动脉粥样硬化病变形成的最初步骤。单核细胞 趋化蛋白-1(MCP-1)是一种多肽趋化因子，在多种环境中发挥重要作用。 在单核细胞募集到血管壁中起重要作用。血管紧张素II (Ang II)是肾素-血管紧张素系统的关键成分，包括血管 氧化应激和第二信使信号介导血管 炎症性事件。PI已经证明：1)大鼠输注 血管紧张素II(Ang II)表现为血管表达增加 炎症基因，如单核细胞趋化蛋白-1在他们的主动脉。2)Ang II也诱导 单核细胞趋化蛋白-1基因在培养的大鼠主动脉平滑肌细胞中的表达 通过一种氧化还原敏感机制。这些数据表明 Ang II可能通过直接刺激血管参与动脉粥样硬化的形成 炎症反应与促进炎性细胞渗入 动脉粥样硬化病变。这个项目的长期目标是 趋化因子基因调控的分子机制研究 在血管系统中的表达，这可能会导致小说的发展 控制这些基因表达的干预性方法。这 这项研究旨在研究分子和信号转导。 血管平滑肌细胞调控血管紧张素Ⅱ介导的单核细胞趋化蛋白-1基因表达的机制 作为一个模范系统。PI将使用分子生物学技术来识别 并对顺式反应元件(S)和反式激活因子进行了表征 血管紧张素转换酶Ⅱ诱导VSMC单核细胞趋化蛋白-1基因表达与S因子有关。《少年派》 也将使用药物干预和基因操作 研究转录因子NK-kB和KB的作用的技术 AP-1在血管紧张素Ⅱ诱导的VSMC MCP-1基因表达中的作用此外，PI 将使用类似的方法来表征特定的氧化剂信号 Ang II诱导VSMC MCP-1基因表达的机制这个 所获得的信息将有助于理解分子和细胞 单核细胞趋化蛋白-1基因在血管平滑肌中表达的调控机制 肌肉细胞，以及2)在设计新的介入方法方面有用 预防和控制动脉粥样硬化等血管炎症过程。

DESCRIPTION: (Adapted from the application) The molecular and cellular mechanisms underlying hypertension as a risk factor for atherosclerosis are poorly understood. Several lines of clinical and experimental evidence suggest a potential role of the renin-angiotensin system in contributing to atherogenesis. Infiltration of monocytes into the vascular wall is a key initial step in the formation of the atherosclerotic lesion. Monocyte chemoattractant protein-1 (MCP-1), is a peptide chemokine that plays an important role in monocyte recruitment into the vessel wall. Angiotensin II (Ang II), a key component of the renin-angiotensin system, incudes vascular oxidative stress and second messenger signals that mediate vascular inflammatory events. The PI has demonstrated: 1) Rats infused with angiotensin II (Ang II) exhibit increased expression of vascular inflammatory genes such as MCP-1 in their aortas. 2) Ang II also induces MCP-1 gene expression in cultured rat aortic smooth muscle cells (VSMCs) through an oxidation-reduction sensitive mechanism. These data suggest that Ang II may contribute to atherogenesis by directly stimulating vascular inflammatory responses and promoting infiltration of inflammatory cells into the atherosclerotic lesion. The long- term goal of this project is to investigate the molecular mechanisms of regulation of chemokine gene expression in the vasculature, which may lead to the development of novel interventional methods for controlling the expression of these genes. This study is designed to investigate the molecular and signal transduction mechanisms that regulate Ang II-mediated MCP-1 gene expression using VSMCs as a model system. The PI will use molecular biology techniques to identify and characterize the cis-response element(s) and the trans-activating factor(s) involved in Ang II-induced MCP-1 gene expression in VSMCs. The PI will also use pharmacological intervention and genetic manipulation techniques to investigate the role of the transcription factors NK-kB and AP-1 in Ang II-induced MCP-1 gene expression in VSMCs. Furthermore, the PI will use similar approaches to characterize the specific oxidant signaling mechanisms involved in Ang II-induced MCP-1 gene expression in VSMCs. The information obtained would 1) help understand the molecular and cellular mechanisms in the regulation of MCP-1 gene expression in vascular smooth muscle cells, and 2) be useful in designing new interventional methods to prevent and control vascular inflammatory processes such as atherosclerosis.