Prevention of high fat diet-induced vascular injury

预防高脂饮食引起的血管损伤

基本信息

批准号：
8440776
负责人：
MING-HUI ZOU
金额：
$ 34.87万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
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：
2010-07-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440776
关键词：
26S proteasome 5&apos -AMP-activated protein kinase AMP-activated protein kinase kinase Adenoviruses Aftercare Aging Aorta Apolipoprotein E Arachidonic Acids Atherosclerosis Attenuated Biological Assay Blood Vessels CaM kinase I activator Cardiovascular Diseases Cardiovascular system Cattle Cells Cessation of life Chronic Clinical Trials Consumption Coronary heart disease Data Diabetes Mellitus Diet Disease Docosahexaenoic Acids Dominant-Negative Mutation Dose Eicosapentaenoic Acid Endothelial Cells Endothelium Epidemiologic Studies Event Fatty acid glycerol esters Fish Oils Functional disorder Genetic Goals Human Hypertension In Vitro Injury Knock-out Laboratories Lesion Low Density Lipoprotein Receptor MG132 Mediating Metabolism Molecular Mus NF-kappa B Nuclear Translocation Obesity Omega-3 Fatty Acids Oxidases Oxidative Stress Patients Peroxisome Proliferator-Activated Receptors Phosphorylation Physiological Polyunsaturated Fatty Acids Prevention Production Proteasome Inhibitor Proteins Relaxation Role STK11 gene Signal Transduction Small Interfering RNA Superoxides TNFRSF5 gene Techniques Testing Time Transactivation Umbilical vein Work activity marker gain of function in vivo insight loss of function multicatalytic endopeptidase complex neutrophil cytosol factor 67K novel overexpression p65 protective effect public health relevance receptor response therapeutic target vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Overwhelming data from epidemiological studies and clinical trials reveal that consumption of fish oils (omega-3 polyunsaturated fatty acids) reduces cardiovascular deaths (CVD) and retards the progression of atherosclerosis in patients with coronary heart diseases. However, the cellular and molecular mechanisms by which omega-3 polyunsaturated fatty acids exert their protective effects remain poorly understood. Exciting data from the applicant's laboratory has revealed that administration of omega-3 polyunsaturated fatty acids significantly increased the phosphorylation of AMPK at Thr172 and AMPK activity. Activation of AMPK suppresses 26S proteasomes, the activation of nuclear factor kappa B, and the expression of NAD(P)H oxidase. Consistently, genetic deletion of AMPK12 in either ApoE knockout (Apo E-/-) or LDL receptor knockout (LDLr-/-) strain markedly increased 26S proteasome activity, I?B degradation, NF:B transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, endothelial dysfunction, and atherosclerosis, all of which were largely suppressed by chronic administration of MG132, a potent and cell permeable proteasome inhibitor. The central hypothesis of the current application is that selective activation of AMPK by omega-3 polyunsaturated fatty acids inhibits 26S proteasomes and NF-?B-mediated overexpression of NAD(P)H oxidase resulting in decreased oxidative stress, a key factor in vascular injury caused by high fat diets (HFD). Comprehensive experimental approaches including pharmacological and genetic means (siRNA and adenoviruses) will be used (1) to establish the essential roles of AMPK activation in omega-3 polyunsaturated fatty acids-induced suppression of NF:B-mediated aberrant expression of NAD(P)H oxidase in endothelial cells; (2) to elucidate the central roles of AMPK and 26S proteasome in omega-3 polyunsaturated fatty acids-induced inhibition on NF:B- mediated overexpression of NAD(P)H oxidase in endothelial cells; (3) to dissect the molecular mechanisms by which AMPK suppresses 26S proteasome activity, and (4) to assess the effects of AMPK on endothelial function and atherosclerosis in mice with the endothelium-specific depletion of AMPK (Tg-Cre-AMPK 11 or 12 (flox/flox), loss-of function) or in mice with the endothelium-specific overexpression of a constitutively active AMPK (Tg-CAAMPK, gain-of-function) in vivo. This powerful combination of in vitro and in vivo techniques and gain-/loss-of-function approaches will yield important insights into how omega-3 polyunsaturated fatty acids protect against cardiovascular diseases. Importantly, completion of the proposed studies will also provide novel insights into whether 26S proteasomes and AMPK are potential therapeutic targets for countering atherosclerosis associated with common diseases including aging, obesity, diabetes, and hypertension.

描述（由申请人提供）：流行病学研究和临床试验的压倒性数据表明，鱼油（欧米茄3多不饱和脂肪酸）的食用可减少心血管死亡（CVD），并阻碍患有冠心病患者的动脉粥样硬化的进展。然而，欧米茄-3多不饱和脂肪酸的细胞和分子机制使它们的保护作用保持不足。申请人实验室的令人兴奋的数据表明，omega-3多不饱和脂肪酸的给药显着增加了THR172和AMPK活性时AMPK的磷酸化。 AMPK的激活抑制26S蛋白酶体，核因子Kappa B的激活和NAD（P）H氧化酶的表达。 Consistently, genetic deletion of AMPK12 in either ApoE knockout (Apo E-/-) or LDL receptor knockout (LDLr-/-) strain markedly increased 26S proteasome activity, I?B degradation, NF:B transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, endothelial dysfunction, and atherosclerosis, all of which were largely长期给药MG132抑制，这是一种有效的细胞渗透性蛋白酶体抑制剂。当前应用的中心假设是，Omega-3多不饱和脂肪酸对AMPK的选择性激活抑制26S蛋白酶体和NF-？B介导的NAD（P）H氧化酶的过表达，导致氧化应激不足，导致高脂肪饮食引起血管损伤的关键因素（HFD）。将使用（包括药理和遗传手段（siRNA和腺病毒））的全面实验方法（1）来确定AMPK激活在omega-3多不饱和脂肪酸诱导的NF：B介导的NAD（p）H氧化酶在内皮细胞中的NAD（P）H氧化酶的异常表达的基本作用；（2）阐明AMPK和26S蛋白酶体在omega-3多不饱和脂肪酸诱导的NF：B-介导的NAD（P）H氧化酶在内皮细胞中的过表达的抑制作用；（3）解剖AMPK抑制26S蛋白酶体活性的分子机制，以及（4）评估AMPK对小鼠内皮功能和动脉粥样硬化的影响，并具有AMPK内皮特异性耗尽的AMPK（TG-CRE-CRE-AMPK 11或12（Flox/Flox），与函数的EndiT eNDIRTITITITIT AMPK（TG-CRE-CRE-AMPK）的影响（Flox/Flox），或者具有函数的过度损失） AMPK（TG-CAAMPK，功能获得）在体内。这种强大的体外和体内技术和功能丧失方法的组合将对omega-3多不饱和脂肪酸如何保护心血管疾病产生重要的见解。重要的是，拟议研究的完成还将提供有关26S蛋白酶体和AMPK是否是抵抗与常见疾病有关的动脉粥样硬化的潜在治疗靶标的新见解，包括衰老，肥胖，糖尿病和高血压。