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）：尽管治疗取得了进展，动脉粥样硬化性心血管疾病（ASCVD）的过早发展仍然是系统性红斑狼疮（狼疮，SLE）患者发病和死亡的主要原因。医生有效治疗这些脆弱患者的能力是有限的，特别是由于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式，以便这些易感患者（通常是年轻女性）能够成为积极预防性干预的目标。我们的实验室发现炎症介质（在系统性红斑狼疮中发现水平升高）与正常胆固醇运输破坏之间存在密切关联。这些介质通过调节细胞脂质稳态的基因表达来干扰动脉粥样硬化胆固醇转运过程。我们进一步证明，植物化学物质白藜芦醇（3,4',5-三羟基反式二苯乙烯）通过增强胆固醇流出和限制体外胆固醇摄取来改善人类巨噬细胞和内皮细胞的胆固醇处理。白藜芦醇是一种存在于葡萄和红酒中的天然抗炎化合物，我们发现它可以减弱特定清道夫受体的表达，上调关键胆固醇流出蛋白的表达，并防止细胞因子介导的这些蛋白水平的有害变化。总体而言，白藜芦醇可防止脂质超载并减少泡沫细胞转化（动脉粥样硬化形成的标志事件）。在培养的人类巨噬细胞中，我们发现白藜芦醇可以防止系统性红斑狼疮血浆对胆固醇外流蛋白的抑制。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，并可能为狼疮人群预防 ASCVD 的治疗干预提供新的靶点。最终，随着我们走向个性化医疗方案，那些最有可能从白藜芦醇中受益的人可能会根据脂质调节基因的药物遗传学测试获得这种膳食补充剂。为了表征白藜芦醇在自身免疫环境中的抗动脉粥样硬化特性所涉及的途径，我们提出了两个目标：1）定义负责白藜芦醇增强胆固醇动员的特定信号系统。根据我们的初步研究，我们专门研究了白藜芦醇和嘌呤核苷腺苷共享的途径，嘌呤核苷腺苷是人体暴露于白藜芦醇后释放的一种有效的心肌保护中间体。 2) 评估白藜芦醇治疗干预（在高脂饮食和正常饮食条件下）对动脉粥样硬化发展、胆固醇转运基因表达谱和 ApoE-/- Fas-/- (lpr/lpr) 中胆固醇通量的影响小鼠，狼疮易感性小鼠动脉粥样硬化模型。为了验证我们的假设，即白藜芦醇通过影响血管壁中的胆固醇流动来阻止动脉粥样硬化的发展，我们将检查脉管系统在考虑进行人体测试之前，先在该动物模型中进行体内试验。