Role of PPAR-gamma in Cerebral Endothelium

描述（由申请人提供）： 因为它是脑血管疾病和中风的主要危险因素，也是认知能力下降的主要原因，所以高血压对大脑有巨大的负面影响。终末器官内皮损伤是多种形式脑血管疾病的基础，具有不同的后果。肾素-血管紧张素系统（RAS）和血管紧张素II（Ang II）在高血压和血管疾病的发病机制中起着重要作用。RAS的有害作用通常是由于Ang II作用于AT 1受体，导致许多下游靶点活化和氧化应激。预防脑血管疾病进展的一个主要障碍是我们对可能有效抑制这些过程的内源性分子和途径的了解有限。我们的试验数据表明，转录因子过氧化物酶体增殖物激活受体（PPAR）与RAS的联系对脑循环有重大影响。使用新型小鼠模型来定义细胞特异性机制，我们的总体目标是确定内皮型过氧化物酶体激活受体是否保护血管紧张素II依赖性疾病模型中的血管系统，并定义介导这些作用的靶点或途径。为了确定在这种细胞类型的作用，我们将检查的假设，干扰内皮细胞的过氧化物酶体增殖体激活受体增强血管生成素II诱导的血管功能障碍和异常血管生长（目的1）。作为该目标的一部分，我们还将确定内皮中野生型PPAR表达的增加是否可以保护内皮免受有害的结构和功能影响。我们的初步数据表明，对内皮PPAR的遗传干扰增加NADPH氧化酶的表达并增强Ang II诱导的血管功能障碍，而野生型PPAR的内皮表达增加抑制Ang II的血管效应。与Ang II相反，RAS可以通过Ang（1-7）的作用发挥有益作用。目的2将阐明以前未知的相互作用，并确定血管紧张素（1-7）及其受体是否是内皮细胞过氧化物酶体增殖物激活受体的靶点。我们将确定是否干扰内皮细胞的过氧化物酶体增殖物激活受体损害血管的血管作用的血管紧张素（1-7）臂的RAS和定义的机制。我们的初步数据支持这一假设。我们认为，过氧化物酶体增殖物激活受体和内皮细胞中的选择性靶点是以前未被认识到的抑制血管紧张素II有害作用的机制的一部分。血管内皮细胞中PPAR和RAS（及其各自靶点）的平衡可能是颈动脉和脑血管疾病发生和进展的主要决定因素。定义PPAR和RAS之间的关键联系可能最终导致血管疾病的更具体的治疗靶向，导致中风和/或有助于阿尔茨海默病和高血压诱导的认知障碍的血管成分。

DESCRIPTION (provided by applicant): Because it is a major risk factor for cerebrovascular disease and stroke and a leading cause of cognitive decline, hypertension has an enormous negative impact on the brain. End-organ damage to endothelium underlies many forms of cerebrovascular disease with diverse consequences. The renin-angiotensin sys- tem (RAS) and angiotensin II (Ang II) play a fundamental role during hypertension and in the pathogenesis of vascular disease. Detrimental effects of the RAS are commonly due to Ang II acting on AT1 receptors resulting in activation of many downstream targets and oxidative stress. A major barrier to progress for preventing cerebrovascular disease has been our limited understanding of endogenous molecules and pathways that may effectively suppress these processes. Our pilot data suggest the transcription factor peroxisome proliferator-activated receptor- (PPAR) has a major influence on the cerebral circulation with links to the RAS. Using novel mouse models to define cell-specific mechanisms, our overall goal is to determine if endothelial PPAR protects the vasculature in Ang II-dependent models of disease and to define targets or pathways that mediate these effects. To define the role of PPAR in this cell type, we will examine the hypothesis that interference with endothelial PPAR augments Ang-II induced vascular dysfunction and abnormal vascular growth (Aim 1). As part of this Aim we will also determine if increased expression of wild-type PPAR in endothelium protects against detrimental structural and functional effects. Our preliminary data suggest genetic interference with endothelial PPAR increases expression of NADPH oxidase and augments Ang II-induced vascular dysfunction while increased endothelial expression of wild- type PPAR inhibits vascular effects of Ang II. In contrast to Ang II, the RAS can exert beneficial effects via the actions of Ang (1-7). Aim 2 will unravel a previously unknown interaction and determine if Ang (1-7) and its receptor are targets of endothelial PPAR. We will determine if interference with endothelial PPAR impairs vascular effects of the Ang (1-7) arm of the RAS and define mechanisms involved. Our preliminary data support this hypothesis. We suggest PPAR and select targets in endothelium are part of a previously unrecognized mechanism that suppresses detrimental effects of Ang II. The balance between PPAR and the RAS (and their respective targets) in endothelium may be a major determinant of the onset and pro- gression of carotid and cerebrovascular disease. Defining key connections between PPAR and the RAS may ultimately lead to more specific therapeutic targeting for vascular disease that leads to stroke and/or contributes to the vascular component of Alzheimers disease and hypertension-induced cognitive impairment.