Aging, Western Diet and Endothelial Dysfunction: Role of NFkB and JNK Activation

描述（由申请人提供）：年龄增长与血管功能障碍和疾病的发生有关。然而，所涉及的机制还不完全清楚。一个新的和基本上未经探索的假设是，“生理抵抗力”的不利影响，我们长期暴露于常见的环境因素随着年龄的增长而下降，从而加剧了由此产生的功能障碍和疾病的风险增加。一个这样的因素可能是“西方”，即，高脂饮食（WD）。本项目的总体目标是研究WD加重年龄相关血管内皮功能障碍的机制。具体而言，我们将研究WD对中年（MA）和老年（O）小鼠血管炎症，氧化应激和细胞凋亡调节中涉及的信号通路的影响。具体目的是（1）测量MA/O小鼠颈动脉中内皮依赖性舒张（EDD）和一氧化氮（NO）的生物利用度，以确定年龄增长是否与促炎、促氧化、促凋亡表型相关，（2）确定WD是否增加促炎和凋亡信号分子的活化;核因子κ B（NF κ B）、c-jun NH 2末端激酶（JNK）和叉头盒O（FoxO），以及（3）确定NF κ B或JNK的抑制是否可以逆转MA/O小鼠中WD相关的血管功能障碍、炎症、氧化应激和细胞凋亡。为此，我们将研究年轻（Y：6-8月龄）、MA（18-20月龄）和O（30-32月龄）雄性B6 D2 F1小鼠。小鼠将被喂食标准食物（NCD，来自脂肪的12%kcal）或定制WD（来自脂肪的40%kcal）。将在离体颈动脉中测量血管内皮功能。将在主动脉裂解物中评估一氧化氮生物利用度和NF κ B、JNK和FoxO的活化。最后，我们将利用NF κ B和JNK的药理学抑制来确定它们在WD相关的血管内皮功能障碍、炎症、氧化应激和MA/O小鼠细胞凋亡中的作用。预期的结果将提供新的见解WD加剧年龄相关的血管功能障碍的机制。 公共卫生相关性：年龄增长和WD消费与血管功能障碍和疾病相关。这项建议旨在确定WD的不良影响是否随着年龄的增长而变得更大，以及可能发生的机制。

DESCRIPTION (provided by applicant): Advancing age is associated with the development of vascular dysfunction and disease. However, the mechanisms involved are incompletely understood. One novel and largely unexplored hypothesis is that "physiological resistance" to the adverse effects of common environmental factors to which we are chronically exposed decreases with aging, thus exacerbating the resulting dysfunction and increased risk of disease. One such factor may be a "Western", i.e., high-fat, diet (WD). The overall goal of this project is to examine the mechanisms by which WD exacerbates age-associated vascular endothelial dysfunction. Specifically, we will examine the effect of WD on signaling pathways involved in the regulation of vascular inflammation, oxidative stress and apoptosis in middle-aged (MA) and older (O) mice. The specific aims are (1) to measure endothelium dependent dilation (EDD) and nitric oxide (NO) bioavailability in the carotid arteries of MA/O mice, to determine if advancing age is associated with a pro- inflammatory, pro-oxidative, pro-apoptotic phenotype, (2) to determine if WD increases the activation of the pro-inflammatory and apoptotic signaling molecules; nuclear factor kappa B (NFkB), c-jun NH2 terminal kinase (JNK), and forkhead box O (FoxO) in MA/O mice and (3) to determine if inhibition of NFkB or JNK can reverse WD-associated vascular dysfunction, inflammation, oxidative stress and apoptosis in MA/O mice. To do so, we will study young (Y: 6-8 mo), MA (18-20 mo) and O (30-32 mo) male B6D2F1 mice. Mice will be fed standard chow (NCD, 12% kcal from fat) or a custom WD (40% kcal from fat). Vascular endothelial function will be measured in isolated carotid arteries. Nitric oxide bioavailability and activation of NFkB, JNK and FoxO will be assessed in aortic lysates. Lastly, we will utilize pharmacological inhibition of NFkB and JNK to determine their roles in WD-associated vascular endothelial dysfunction, inflammation, oxidative stress and apoptosis in MA/O mice. The expected results will provide novel insight into the mechanisms by which WD exacerbates age-associated vascular dysfunction. PUBLIC HEALTH RELEVANCE: Advancing age and consumption of a WD are associated with vascular dysfunction and disease. This proposal aims to determine if the adverse effects of WD become greater with advancing age and the mechanisms by which this may occur.