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危险因素的潜在机制是 不太了解。 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 单核细胞向血管壁的浸润是一个关键 动脉粥样硬化病变形成的初始步骤。 单核细胞 趋化蛋白-1（MCP-1）是一种肽趋化因子， 在单核细胞募集到血管壁中的重要作用。 血管紧张素II (Ang II），肾素-血管紧张素系统的关键成分，包括血管紧张素II， 氧化应激和第二信使信号， 炎症事件。 PI已证明：1）输注以下药物的大鼠 血管紧张素II（Ang II）表现出血管紧张素II表达增加， 炎症基因，如MCP-1。 2)血管紧张素II还诱导 MCP-1基因在培养大鼠主动脉平滑肌细胞中的表达 通过氧化还原敏感机制。 这些数据表明 血管紧张素Ⅱ可能通过直接刺激血管紧张素Ⅱ受体， 炎症反应和促进炎性细胞浸润 动脉粥样硬化病变。 这个项目的长期目标是 探讨趋化因子基因调控的分子机制 在脉管系统中表达，这可能导致新的 控制这些基因表达的干预方法。 这 本研究旨在探讨细胞凋亡的分子和信号转导机制 血管紧张素II介导的MCP-1基因表达的调控机制 作为一个模型系统。 PI将使用分子生物学技术来识别 并表征顺式反应元件和反式激活元件， 血管紧张素II诱导的血管平滑肌细胞MCP-1基因表达的相关因子。 的PI 也会使用药物干预和基因操作 研究转录因子NK-kB和 AP-1在血管紧张素II诱导的血管平滑肌细胞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传导 血管紧张素II诱导的血管平滑肌细胞MCP-1基因表达的机制。 的 获得的信息将有助于1）了解分子和细胞 血管平滑肌细胞MCP-1基因表达的调控机制 肌细胞，2）在设计新的介入方法中是有用的， 预防和控制血管炎症过程，如动脉粥样硬化。

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.