Resveratrol as an Innovative Cardiovascular Therapeutic Strategy in Lupus

白藜芦醇作为狼疮的创新心血管治疗策略

基本信息

批准号：
8444765
负责人：
ALLISON B REISS
金额：
$ 16.12万
依托单位：
NYU WINTHROP HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444765
关键词：
Accounting Acute Address Adenosine Adenosine A2A Receptor Adverse effects Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antioxidants Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Attenuated Autoimmune Diseases Autoimmune Process Biological Preservation Blood Vessels Bone Marrow Cardiotonic Agents Cardiovascular Diseases Cardiovascular system Carrier Proteins Cell Culture Techniques Cells Cholesterol Cholesterol Homeostasis Clinical Consumption Cyclic AMP Deposition Development Diet Disease Endothelium Equilibrium Event Excision Exhibits Exposure to Fatty acid glycerol esters Fibrosis Foam Cells Functional disorder Gene Expression Gene Expression Profile Genes Goals Grapes Homeostasis Human Immune response In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferons Intervention Kidney Knock-out Laboratories Lead Lesion Life Light Lipids Liver Lupus Mediating Mediator of activation protein Medical Methotrexate Mitogen-Activated Protein Kinases Modality Modeling Molecular Morbidity - disease rate Mus Myocardial Myocardial Infarction Nature Outcome Pathway interactions Patients Pattern Persons Pharmaceutical Preparations Physicians Phytochemical Plants Plasma Population Process Property Proteins Purine Nucleosides Receptor Activation Regimen Regulation Research Resveratrol Rheumatoid Arthritis Risk Safety Serum Severities Signal Pathway Signal Transduction Skin Staging Stilbenes Stimulus Stroke System Systemic Lupus Erythematosus Testing Therapeutic Therapeutic Intervention Therapeutic Uses Transport Process Vulnerable Populations Work atherogenesis atheroprotective base cardiovascular risk factor cell transformation cholesterol control cholesterol trafficking cytokine dietary supplements improved in vivo in vivo Model innovation macrophage monocyte mortality mouse model new therapeutic target novel novel strategies novel therapeutics oxidized low density lipoprotein pharmacogenetic testing premature prevent protein expression public health relevance receptor red wine research clinical testing response scavenger receptor therapeutic target uptake young woman

项目摘要

DESCRIPTION (provided by applicant): Despite advances in treatment, premature development of atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality in persons living with systemic lupus erythematosus (lupus, SLE). The ability of the physician to treat these vulnerable patients effectively is limited, particularly du to the inadequacy of their response to classic medications such as statins. There is a clear need to develop novel therapeutic modalities so that these susceptible patients, who are often young women, can be targeted for aggressive preventative interventions. Our laboratory has uncovered a strong association between inflammatory mediators (found at elevated levels in SLE) and disruption of normal cholesterol trafficking. These mediators interfere with atheroprotective cholesterol transport processes by dysregulating expression of genes that control cellular lipid homeostasis. We further demonstrated that the phytochemical resveratrol (3,4',5- trihydroxytrans-stilbene) improves cholesterol handling in human macrophages and endothelium by enhancing cholesterol efflux and limiting cholesterol uptake in vitro. Resveratrol is a natural anti-inflammatory compound present in grapes and red wine that we have found attenuates expression of specific scavenger receptors, upregulates expression of crucial cholesterol efflux proteins and prevents cytokine-mediated injurious changes in the level of these proteins. Overall, resveratrol acts to prevent lipid overload and decrease foam cell transformation, a hallmark event in atherogenesis. In cultured human macrophages we have shown that resveratrol can prevent suppression of cholesterol efflux proteins by SLE plasma. We hypothesize that resveratrol can correct adverse effects of inflammatory processes on cellular cholesterol homeostasis and may provide a novel target for therapeutic intervention to prevent ASCVD in the lupus population. Ultimately, as we move toward personalized medical regimens, those most likely to benefit from resveratrol may be given this dietary supplement based on pharmacogenetic tests of lipid-regulating genes. To characterize the pathways involved in the anti-atherogenic properties of resveratrol in the autoimmune setting we propose 2 aims: 1) Define the specific signaling systems responsible for the enhancement of cholesterol mobilization by resveratrol. Based on our preliminary studies, we look specifically at pathways shared by resveratrol and the purine nucleoside adenosine, a potent intermediate of myocardial preservation released in humans upon exposure to resveratrol. 2) Evaluate the impact of therapeutic intervention with resveratrol (under conditions of both high fat diet and normal chow diet) on atherosclerosis development, cholesterol transport gene expression profile and cholesterol flux in the ApoE-/- Fas-/- (lpr/lpr) mouse, a lupus susceptible murine model of atherosclerosis. To validate our hypothesis that resveratrol impedes development of atherosclerosis via effects on cholesterol flux in the vessel wall, we will examine the vasculature in vivo in this animal model prior to consideration of human testing.

描述（由申请人提供）：尽管治疗进展，但动脉粥样硬化心血管疾病（ASCVD）的过早发展仍然是患有全身性红斑狼疮的人发病和死亡率的主要原因（狼疮，SLE）。医生有效治疗这些脆弱患者的能力受到限制，尤其是对他们对他汀类药物等经典药物的反应不足。显然需要开发新的治疗方法，以便这些经常是年轻女性的易感患者可以作为积极的预防干预措施。我们的实验室发现了炎症介质（在SLE的水平升高）与正常胆固醇贩运的中断之间存在密切的关联。这些介质通过控制细胞脂质稳态的基因的表达来干扰动脉保护胆固醇的转运过程。我们进一步证明，植物化学白藜芦醇（3,4'，5-三羟基trans-stilbene）通过增强胆固醇外排和限制体外胆固醇的胆固醇，改善人类巨噬细胞和内皮的胆固醇处理。白藜芦醇是葡萄和红酒中存在的一种天然抗炎化合物，我们发现它会减弱特定的寻宝受体的表达，上调至关重要的胆固醇外排蛋白的表达，并阻止细胞因子介导的这些蛋白质水平上的有害变化。总体而言，白藜芦醇可防止脂质过载并减少泡沫细胞转化，这是动脉粥样硬化中的标志性事件。在培养的人类巨噬细胞中，我们表明白藜芦醇可以防止SLE血浆抑制胆固醇外排蛋白。我们假设白藜芦醇可以纠正炎症过程对细胞胆固醇稳态的不利影响，并可能为防止狼疮种群的ASCVD提供新的治疗性干预靶标。最终，随着我们朝着个性化的医疗方案迈进，最有可能从白藜芦醇中受益的医疗方案可能会根据脂质调节基因的药物遗传学测试给予这种饮食补充剂。为了表征白藜芦醇在自身免疫环境中涉及的抗动脉生育特性的途径，我们提出2个目标：1）定义负责增强白藜芦醇胆固醇动员的特定信号系统。根据我们的初步研究，我们专门研究白藜芦醇和嘌呤核苷腺苷共享的途径，这是在暴露于白藜芦醇时在人类中释放的心肌保存的有效中间体。 2）评估白藜芦醇（在高脂肪饮食和正常食物饮食的条件下）对动脉粥样硬化发展，胆固醇转运基因表达谱和胆固醇通量对ApoE-/ - FAS - / - / - （LPR/LPR）小鼠的影响，评估白藜芦醇的治疗干预措施（在高脂肪饮食和正常食物饮食的条件下），lupus小鼠，卢普斯up usipsible Mirine Murine模型。为了验证我们的假设，即白藜芦醇通过对容器壁中胆固醇通量的影响阻碍动脉粥样硬化的发展，我们将检查脉管系统在考虑人类测试之前，在该动物模型中进行体内。