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

描述（由申请人提供）：年龄的增长与血管功能障碍和疾病的发展有关。然而，所涉及的机制尚不完全清楚。一种新的、基本上未被探索的假设是，对我们长期暴露于常见环境因素的不利影响的“生理抵抗力”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风险的增加。其中一个因素可能是“西方”，即高脂肪饮食（WD）。该项目的总体目标是研究WD加剧年龄相关血管内皮功能障碍的机制。具体来说，我们将研究WD对中年（MA）和老年(O)小鼠血管炎症、氧化应激和凋亡调控信号通路的影响。具体目的是：(1)测量MA/O小鼠颈动脉内皮依赖性扩张（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症、促氧化、促凋亡表型相关；(2)确定WD是否增加促炎症和凋亡信号分子的激活；核因子κ B （NFkB）、c-jun NH2末端激酶（JNK）和叉头盒O （FoxO）在MA/O小鼠中的表达，以及(3)确定NFkB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、氧化应激和凋亡。为此，我们将研究幼年（Y: 6-8个月）、MA（18-20个月）和O（30-32个月）雄性B6D2F1小鼠。小鼠将被喂食标准食物（非cd， 12%卡路里来自脂肪）或定制WD（40%卡路里来自脂肪）。血管内皮功能将在分离的颈动脉中测量。将在主动脉裂解液中评估一氧化氮的生物利用度和NFkB、JNK和FoxO的激活。最后，我们将利用NFkB和JNK的药理抑制来确定它们在MA/O小鼠中与wd相关的血管内皮功能障碍、炎症、氧化应激和凋亡中的作用。预期的结果将为WD加剧与年龄相关的血管功能障碍的机制提供新的见解。

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.