Role of PPAR-gamma in Cerebral Endothelium

描述(由申请人提供)： 由于高血压是脑血管疾病和中风的主要风险因素，也是认知能力下降的主要原因，因此高血压对大脑有巨大的负面影响。终末器官对内皮的损伤是多种形式脑血管疾病的基础，其后果各不相同。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基础性作用。RAS的不利影响通常是由于Ang II作用于AT1受体，导致许多下游靶点的激活和氧化应激。在预防脑血管疾病方面取得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。我们的初步数据表明，转录因子过氧化物酶体增殖物激活受体(PPAR)与RAS有关，对脑循环有重要影响。使用新的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PPAR是否在Ang II依赖的疾病模型中保护血管系统，并确定介导这些影响的靶点或途径。为了确定PPAR在这种细胞类型中的作用，我们将检验这样的假设，即干扰内皮细胞PPAR会增强Ang-II诱导的血管功能障碍和异常血管生长(目标1)。作为这一目标的一部分，我们还将确定内皮细胞野生型PPAR表达的增加是否会保护血管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的遗传干扰增加了NADPH氧化酶的表达，增强了Ang II诱导的血管功能障碍，而内皮细胞野生型PPAR表达的增加抑制了Ang II的血管效应。与Ang II相比，RAS可以通过Ang(1-7)发挥有益的作用。Aim 2将揭开一个以前未知的相互作用，并确定Ang(1-7)及其受体是否为内皮PPAR的靶标。我们将确定对内皮PPAR的干扰是否损害RAS的Ang(1-7)臂的血管效应，并确定相关的机制。我们的初步数据支持这一假设。我们认为PPAR和血管内皮细胞的选择性靶点是抑制血管紧张素Ⅱ的有害作用的未知机制的一部分。PPAR和血管内皮细胞RAS(及其各自的靶点)之间的平衡可能是颈动脉和脑血管疾病发生和发展的主要决定因素。明确PPAR和RAS之间的关键联系可能最终导致针对导致中风和/或导致阿尔茨海默病和高血压引起的认知障碍的血管疾病的更具体的治疗靶向。

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.