Mechanisms of Vascular Dysfunction in Diet-Induced Obesity

饮食引起的肥胖血管功能障碍的机制

• 批准号: 7987104
• 负责人: SEAN P DIDION
• 金额: $ 37.25万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987104
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Blood Vessels; Cardiovascular Diseases; Carotid Artery Diseases; Clinical; DNA Repair; Data; Development; Diet; Eating; Event; Fatty acid glycerol esters; Functional disorder; Future; Genetic; Goals; Human; Incidence; Inflammation; Inflammatory; Interleukin-10; Interleukin-6; Link; Mediating; Modeling; Molecular; Mus; Nuclear Protein; Nuclear Proteins; Obesity; Oxidases; Oxidative Stress; Phenotype; Plasma; Poly(ADP-ribose) Polymerases; Protein Isoforms; Public Health; Research Design; Risk Factors; Role; Source; Stroke; Superoxides; Testing; United States; cardiovascular disorder risk; cytokine; design; feeding; human NOS3 protein; improved; innovation; insight; mouse model; novel; protective effect; public health relevance; response; tool; vascular inflammation

DESCRIPTION (provided by applicant): Obesity and obesity-related risk factors are associated with an increased risk of cardiovascular disease and events including carotid artery disease and stroke. The most common type of obesity in humans is diet-induced obesity. Inappropriate food-intake, particularly of a diet high in fat, is the primary cause of diet-induced obesity in humans. Although the incidence of obesity is increasing in the United States, very little is known regarding the effects of obesity on the vasculature and even less is known regarding mechanisms that limit or contribute to oxidative stress or endothelial dysfunction in blood vessels. Thus, the overall goal of this proposal is to examine potential mechanisms that contribute to oxidative stress and endothelial-dysfunction in a model of diet-induced obesity produced by a diet high in fat and one that recapitulates the development of obesity in humans. First, studies are proposed to examine the potential role of NAD(P)H oxidase as an important source of superoxide that contributes to vascular dysfunction produced by a high fat diet. Second, studies are proposed to determine whether IL-6, a potent pro-inflammatory cytokine, contributes to oxidative stress and vascular dysfunction produced by a high fat diet. Studies are designed to examine whether increases in IL-6 that occur with obesity are linked to enhanced NA(D)PH oxidase expression and/or activity. Conversely, studies are proposed to determine whether IL-10, a potent anti-inflammatory cytokine, limits oxidative stress and vascular dysfunction in response to a high fat diet. Studies are designed to examine whether the protective effect of IL-10 in limiting oxidative stress and endothelial dysfunction in obesity is mediated reductions in NAD(P)H oxidase activity and/or reduction in IL-6. Third, studies are proposed to examine whether deficiency of PARP-1, a downstream target of oxidative stress, limits the increase in oxidative stress and endothelial dysfunction in response to a high fat diet via reductions in NAD(P)H oxidase or IL-6 expression and/or increases in IL-10 or endothelial nitric oxide synthase. Our preliminary data support these hypotheses. Examination of mechanisms that contribute to or limit endothelial dysfunction in obesity are important because endothelial dysfunction has emerged as an independent clinical predictor of future cardiovascular disease and events. The results derived from the proposed studies should provide novel insight into mechanisms related to oxidative stress and endothelial dysfunction in response to diet-induced obesity. PUBLIC HEALTH RELEVANCE: Obesity is associated with an increased incidence of cardiovascular disease and events including carotid artery disease and stroke. Studies in this proposal are designed to examine the role of NAD(P)H oxidase, interleukin-6, interleukin-10, and poly(ADP)- ribose polymerase in contributing to oxidative stress and vascular dysfunction in diet- induced obesity. Results from these studies should provide new insight into mechanisms related to oxidative stress and vascular dysfunction in response to a diet high in fat and are aimed at improving public health.

描述（由申请人提供）：肥胖和肥胖相关的危险因素与心血管疾病和事件（包括颈动脉疾病和中风）的风险增加有关。人类最常见的肥胖类型是饮食引起的肥胖。不适当的食物摄入，特别是高脂肪饮食，是人类饮食引起肥胖的主要原因。尽管肥胖在美国的发病率正在上升，但人们对肥胖对血管系统的影响知之甚少，对限制或促进血管氧化应激或内皮功能障碍的机制了解得更少。因此，本提案的总体目标是在高脂肪饮食和概括人类肥胖发展的饮食诱导肥胖模型中，研究导致氧化应激和内皮功能障碍的潜在机制。首先，研究人员提出研究NAD(P)H氧化酶作为高脂肪饮食引起血管功能障碍的超氧化物的重要来源的潜在作用。其次，研究旨在确定IL-6（一种强效的促炎细胞因子）是否有助于高脂肪饮食产生的氧化应激和血管功能障碍。研究旨在检查肥胖患者IL-6的增加是否与NA(D)PH氧化酶表达和/或活性增强有关。相反，研究建议确定IL-10，一种有效的抗炎细胞因子，是否限制高脂肪饮食的氧化应激和血管功能障碍。研究旨在研究IL-10在限制肥胖氧化应激和内皮功能障碍中的保护作用是否介导了NAD(P)H氧化酶活性的降低和/或IL-6的降低。第三，研究人员提出研究PARP-1（氧化应激的下游靶点）的缺乏是否通过降低NAD(P)H氧化酶或IL-6表达和/或增加IL-10或内皮一氧化氮合酶来限制高脂肪饮食反应中氧化应激和内皮功能障碍的增加。我们的初步数据支持这些假设。研究导致或限制肥胖患者内皮功能障碍的机制非常重要，因为内皮功能障碍已成为未来心血管疾病和事件的独立临床预测指标。这些研究的结果将为研究饮食引起的肥胖与氧化应激和内皮功能障碍相关的机制提供新的见解。