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

衰老、西方饮食和内皮功能障碍：NFkB 和 JNK 激活的作用

基本信息

批准号：
8136352
负责人：
Lisa A Lesniewski
金额：
$ 13.54万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136352
关键词：
Adult Adverse effects Age Aging Animals Apoptosis Apoptotic Atherosclerosis Behavior Biological Availability Blood Vessels Boxing Carotid Arteries Clinical Trials Consumption Custom Data Development Diabetes Mellitus Diet Disease Elderly Endothelium Environmental Risk Factor Exposure to Fatty acid glycerol esters Functional disorder Future Goals Human Inflammation Inflammatory Intervention JUN gene Life Style Measures Metabolic Molecular Mus NF-kappa B Nitric Oxide Oxidative Stress Phenotype Physiological Regulation Resistance Role Signal Pathway Signal Transduction Signaling Molecule Testing Tissues United States National Institutes of Health Work base cardiovascular disorder risk disorder risk feeding insight male middle age novel obesity risk prevent public health relevance stress-activated protein kinase 1 vascular endothelial dysfunction vascular inflammation

项目摘要

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.

描述（由申请人提供）：年龄增长与血管功能障碍和疾病的发展相关。然而，所涉及的机制尚不完全清楚。一种新颖且尚未被探索的假设是，对我们长期暴露的常见环境因素的不利影响的“生理抵抗力”会随着年龄的增长而降低，从而加剧由此产生的功能障碍并增加患病风险。其中一个因素可能是“西方”饮食，即高脂肪饮食（WD）。该项目的总体目标是研究 WD 加剧与年龄相关的血管内皮功能障碍的机制。具体来说，我们将检查 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所涉及的信号通路的影响。具体目标是 (1) 测量 MA/O 小鼠颈动脉中的内皮依赖性扩张 (EDD) 和一氧化氮 (NO) 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，(2) 确定 WD 是否会增加促炎和凋亡信号分子的激活； MA/O 小鼠中的核因子 kappa B (NFkB)、c-jun NH2 末端激酶 (JNK) 和叉头盒 O (FoxO) 以及 (3) 确定抑制 NFkB 或 JNK 是否可以逆转 WD 相关的血管功能障碍， MA/O 小鼠的炎症、氧化应激和细胞凋亡。为此，我们将研究年轻（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（NCD，12% kcal 来自脂肪）或定制 WD（40% kcal 来自脂肪）。将在分离的颈动脉中测量血管内皮功能。将评估主动脉裂解物中的一氧化氮生物利用度以及 NFkB、JNK 和 FoxO 的激活。最后，我们将利用 NFkB 和 JNK 的药理学抑制作用来确定它们在 MA/O 小鼠中 WD 相关血管内皮功能障碍、炎症、氧化应激和细胞凋亡中的作用。预期结果将为 WD 加剧与年龄相关的血管功能障碍的机制提供新的见解。公众健康相关性：年龄的增长和 WD 的消耗与血管功能障碍和疾病有关。该提案旨在确定 WD 的不利影响是否会随着年龄的增长而变得更大，以及这种情况可能发生的机制。