Hypertension, Hydrogen Peroxide and Vascular Inflammation

描述(申请人提供)：高血压向动脉壁传递一系列复杂的体液和机械信号，导致炎症状态的发展。最近的研究表明，活性氧的产生在高血压血管病理的发病机制中起着中心作用。在这一应用中，我们建议检验这一假设，即在高血压的背景下，血管平滑肌细胞、内皮细胞和/或常驻巨噬细胞局部产生的过氧化氢是高血压动脉壁炎症反应中的关键信号事件。为了实现这一总体目标，我们开发了一种新的转基因小鼠，它将允许组织特异性地过度表达过氧化氢酶。通过这些研究，我们将能够在细胞水平上修饰局部过氧化氢的产生，并确定随后对活性氧产生、炎症基因表达和高血压诱导的动脉粥样硬化发展的影响。提出的具体目的是：1：确定过氧化氢酶在高血压诱导的炎症和动脉粥样硬化发展中的作用。II：研究巨噬细胞特异性过氧化氢酶过度表达对高血压血管后果的比较效应。III：确定内皮特异性过氧化氢酶过表达在血管功能、炎症和高血压诱导的动脉粥样硬化进展中的潜在功能贡献。公共卫生相关性：高血压是当今美国的一个主要健康问题。高血压的病理后果是多种多样的，包括动脉粥样硬化、中风、心力衰竭、肾衰竭和其他终末器官疾病。这项应用中的拟议研究将调查局部过氧化氢产生在血管炎症反应中的潜在作用，以努力确定过氧化氢在高血压血管疾病发病机制中的因果作用。

DESCRIPTION (provided by applicant): Hypertension imparts a series of complex humoral and mechanical signals to the arterial wall that result in the development of an inflammatory state. Recent studies have implicated the production of reactive oxygen species as central to the pathogenesis of hypertensive vascular pathology. In this application, we propose to test the hypothesis that in the setting of hypertension, local production of hydrogen peroxide by vascular smooth muscle cells, endothelial cells and/or resident macrophages is a pivotal signaling event in the inflammatory responses that occur in the hypertensive arterial wall. To accomplish this overall objective we have developed a novel transgenic mouse that will allow tissue-specific overexpression of catalase. Through these studies we will be able to modify local H2O2 production at the cellular level and determine the subsequent effects on production of reactive oxygen species, inflammatory gene expression and the development of hypertension-induced atherosclerosis. The proposed specific aims are: I: To determine the effects of smooth muscle-specific overexpression of catalase on the development of hypertension-induced inflammation and atherosclerosis. II: Examine the comparative effects of macrophage-specific overexpression of catalase on the vascular consequences of hypertension. III: To determine the potential functional contributions endothelial-specific overexpression of catalase on vascular function, inflammation and the progression of hypertension-induced atherosclerosis. PUBLIC HEALTH RELEVANCE: Hypertension is a major health problem in the United States today. The pathological consequences of hypertension are myriad and include atherosclerosis, stroke, heart failure, kidney failure and other end organ disease. The proposed studies in this application will investigate the potential role of localized H2O2 production in vascular inflammatory responses in an effort to define the causal role of H2O2 in the pathogenesis of hypertensive vascular disease.