Cytochrome P4501A1 and Vascular Injury

细胞色素 P4501A1 与血管损伤

• 批准号: 8203455
• 负责人: Mary K Walker
• 金额: $ 21.12万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203455
• 关键词: Address; Adult; Angiotensin II; Angiotensin II Receptor; Angiotensinogen; Antihypertensive Agents; Antioxidants; Attenuated; Blood Circulation; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cell Line; Chemicals; Child; Chronic; Complex Mixtures; Coronary heart disease; Cytochromes; Data; Development; Drug Delivery Systems; Endothelial Cells; Endothelium; Environmental Tobacco Smoke; Enzyme Induction; Enzymes; Exposure to; Free Radicals; Functional disorder; Hypertension; In Vitro; Individual; Injury; Lead; Lung; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator of activation protein; Mesenteric Arteries; Mesentery; Metabolism; Methods; Mus; Nitric Oxide; Oxidative Stress; Pathway interactions; Peripheral Vascular Diseases; Pharmacotherapy; Plasma; Prostaglandin-Endoperoxide Synthase; Reactive Oxygen Species; Renin; Renin-Angiotensin System; Reporting; Risk Factors; Signal Transduction; Source; Stroke; Structure; Testing; Tissues; Tobacco smoke; Transgenic Mice; Transgenic Organisms; Vascular Diseases; Vascular Endothelium; Vasoconstrictor Agents; arteriole; blood pressure regulation; cardiovascular injury; cell injury; cell type; chemical addition; cigarette smoking; constriction; hemodynamics; high risk; in vivo; innovation; mouse model; non-smoking; novel; overexpression; oxidation; prevent; response; vasoconstriction

DESCRIPTION (provided by applicant): More than one billion people worldwide smoke cigarettes. In addition, it is estimated that there are at least 125 million children and non-smoking adults exposed to secondhand smoke in the U.S. alone. Both active and passive exposure to tobacco smoke (TS) is a major risk factor for cardiovascular disease, including hypertension. Cardiovascular injury induced by TS is mediated, in part, by oxidative stress. While TS is a source of free radicals, it also activates endogenous pathways that generate reactive oxygen species (ROS). One enzyme that is a significant source of ROS and is highly induced in the vasculature by chemicals in TS is cytochrome P4501A1 (CYP1A1). While the contribution of CYP1A1 induction to TS-induced cancer has been extensively studied, there have been no studies investigating the contribution of endothelial CYP1A1 induction to TS-induced vascular dysfunction and altered hemodynamics in vivo. Since TS is a highly complex mixture of chemicals, it is difficult to dissect out the contribution or mechanism of any single downstream pathway. To tackle this challenge we have developed a novel transgenic mouse model that allows for conditional over expression of CYP1A1 in the vasculature to address the innovative proposal that CYP1A1 induction is an independent risk factor for vascular dysfunction and hypertension in vivo. Our new preliminary data show that over expression of CYP1A1 solely in endothelial cells induces hypertension and exposure of mice to an individual chemical in TS may lead to activation of the renin-angiotensin system (RAS), a major regulator of vascular function and blood pressure. Thus, we will test the hypothesis that over expression of CYP1A1 in vascular endothelium significantly increases ROS which induce vascular dysfunction and angiotensin (Ang) II-dependent hypertension. This hypothesis will be tested in two aims where we will (Aim 1) establish the contribution of ROS and Ang II to hypertension induced by CYP1A1 over expression in vascular endothelium by multiple measurements of ROS and by measuring blood pressure with radiotelemetry 1 treatments with antioxidants or an Ang II receptor blocker, and (Aim 2) elucidate the mechanism by which endothelial CYP1A1 over expression disrupts vascular function independently of increases in blood pressure by evaluating endothelial-dependent dilation and constriction in mesenteric arteries ex vivo prior to increases in blood pressure. This proposal will establish the degree to which induction of endothelial CYP1A1 is an independent mediator of vascular dysfunction and altered hemodynamics in vivo and will elucidate its potential as a drug target to prevent vascular disease induced by both active and passive TS exposure. PUBLIC HEALTH RELEVANCE: Individuals that smoke cigarettes or are exposed to secondhand smoke are at much higher risk for developing cardiovascular disease, including coronary heart disease, peripheral vascular disease, and stroke. Tobacco smoke contains chemicals which increase the expression of cytochrome P4501A1 in the cells that line the blood vessels. This enzyme is a significant source of reactive oxygen species, which can cause vascular injury. Thus, to establish the degree to which induction of this enzyme mediates vascular injury and to elucidate its potential as a drug target to prevent vascular disease induced by exposure to tobacco smoke, we developed a novel transgenic mouse model that allows for cell type-specific over expression of CYP1A1.

描述（由申请人提供）：全世界有超过十亿人吸烟。此外，据估计，仅在美国就有至少 1.25 亿儿童和不吸烟的成年人接触二手烟。主动和被动接触烟草烟雾（TS）都是心血管疾病（包括高血压）的主要危险因素。 TS 引起的心血管损伤部分是由氧化应激介导的。虽然 TS 是自由基的来源，但它也会激活产生活性氧 (ROS) 的内源途径。细胞色素 P4501A1 (CYP1A1) 是一种酶，它是 ROS 的重要来源，并且在 TS 中的化学物质在脉管系统中高度诱导。虽然 CYP1A1 诱导对 TS 诱导的癌症的贡献已被广泛研究，但尚无研究调查内皮 CYP1A1 诱导对 TS 诱导的血管功能障碍和体内血流动力学改变的贡献。由于 TS 是一种高度复杂的化学混合物，因此很难剖析任何单一下游途径的贡献或机制。为了应对这一挑战，我们开发了一种新型转基因小鼠模型，允许 CYP1A1 在脉管系统中条件性过度表达，以解决 CYP1A1 诱导是体内血管功能障碍和高血压的独立危险因素这一创新提议。我们的新初步数据表明，CYP1A1 仅在内皮细胞中过度表达会诱发高血压，而小鼠暴露于 TS 中的某种化学物质可能会导致肾素-血管紧张素系统 (RAS) 的激活，肾素-血管紧张素系统 (RAS) 是血管功能和血压的主要调节因子。因此，我们将检验以下假设：血管内皮细胞中 CYP1A1 的过度表达会显着增加 ROS，从而诱导血管功能障碍和血管紧张素 (Ang) II 依赖性高血压。这一假设将在两个目标上进行检验，我们将（目标 1）通过多次测量 ROS 并通过无线电遥测测量血压来确定 ROS 和 Ang II 对血管内皮 CYP1A1 过度表达诱导的高血压的影响 1 使用抗氧化剂或 Ang II 受体阻滞剂进行治疗，（目标 2）阐明内皮 CYP1A1 过度表达破坏血管的机制 通过评估血压升高之前离体肠系膜动脉的内皮依赖性扩张和收缩，功能独立于血压升高。该提案将确定内皮 CYP1A1 的诱导在多大程度上是血管功能障碍和体内血流动力学改变的独立介质，并将阐明其作为预防主动和被动 TS 暴露引起的血管疾病的药物靶点的潜力。 公共卫生相关性：吸烟或接触二手烟的人患心血管疾病的风险要高得多，包括冠心病、外周血管疾病和中风。烟草烟雾中含有的化学物质可以增加血管内壁细胞中细胞色素 P4501A1 的表达。这种酶是活性氧的重要来源，可导致血管损伤。因此，为了确定这种酶的诱导介导血管损伤的程度，并阐明其作为预防烟草烟雾诱发血管疾病的药物靶点的潜力，我们开发了一种新型转基因小鼠模型，该模型允许细胞类型特异性过度表达 CYP1A1。