Mechanisms Linking Joint Inflammation and Atherosclerosis in Rheumatoid Arthritis

类风湿关节炎中关节炎症和动脉粥样硬化的联系机制

• 批准号: 8818588
• 负责人: Christina Charles-Schoeman
• 金额: $ 57.56万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-15 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818588
• 关键词: Animal Model; Antiatherogenic; Antioxidants; Arthritis; Atherosclerosis; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Cholesterol; Clinical; Clinical Research; Clinical Trials; Collagen-Induced Arthritis; Data; Development; Discipline of Nuclear Medicine; Disease; Functional disorder; Gene Deletion; General Population; High Density Lipoproteins; Inflammation; Inflammatory Arthritis; Intervention; Joints; Lead; Lectin; Link; Low Density Lipoprotein Receptor; Low Density Lipoprotein oxidation; Master' s Degree; Measures; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; Paraoxonase 1; Pathogenesis; Pathway interactions; Patients; Peptides; Positron-Emission Tomography; Prevention strategy; Primary Prevention; Proteins; Proteomics; Research Personnel; Research Project Grants; Rheumatoid Arthritis; Rheumatology; Risk; Risk Assessment; Rosa; Signal Transduction; Staging; Synovial Membrane; Testing; Therapeutic; Translational Research; Ultrasonography; United States National Institutes of Health; Work; cardiovascular risk factor; cohort; fluorodeoxyglucose; follow-up; improved; in vitro Assay; intimal medial thickening; member; mimetics; mortality; mouse model; novel; novel marker; overexpression; oxidized low density lipoprotein; prevent; prospective; public health relevance

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading killer of patients with rheumatoid arthritis (RA) who have a 2-3 fold increased risk of myocardial infarction compared to members of the general population. Traditional cardiovascular (CV) risk factors alone do not accurately predict CVD in RA patients and therefore adequate primary prevention strategies are lacking. Systemic inflammation from active RA is strongly associated with CV risk in RA patients, but mechanisms by which inflammation increases CV morbidity and mortality are poorly understood. High density lipoprotein (HDL) is an anti-atherogenic molecule that regulates systemic inflammation by promoting cholesterol efflux and preventing oxidation of low density lipoproteins (LDL). We have previously demonstrated that HDL function is impaired and significantly associated with both disease activity and systemic inflammation, in patients with RA. We further showed that active RA leads to oxidative and protein changes in HDL resulting in dysfunctional HDL. Oxidized low density lipoproteins (ox-LDL) have been directly implicated in the pathogenesis of RA through signaling via the lectin-like ox-LDL receptor 1 (LOX- 1) in the joint synovium. Our preliminary results suggest that modulation of HDL function by increasing HDL's ability to prevent oxidation of LDL is associated with improvement in arthritis activity. We hypothesize that modulation of HDL function represents a novel pathway through which to both decrease arthritis activity and improve CV risk in patients with RA. We will test our hypothesis under two specific aims. In aim 1, we will evaluate whether modulation of HDL function using HDL mimetic peptides can reduce atherosclerosis and joint inflammation in a recently established mouse model of RA. We will also modulate HDL function by paraoxonase 1 (PON1) gene deletion and overexpression to evaluate the effects on arthritis activity and atherosclerosis in this model. In aim 2, we will determine whether abnormal HDL function contributes to increased CV risk in a carefully characterized, prospective cohort of over 200 RA patients using in vitro assays of HDL function and targeted HDL proteomics and lipidomics. CV risk will be assessed by the progression of carotid atherosclerosis over three year follow-up and by carotid plaque inflammation using positron emission tomography with fluorodeoxyglucose (FDG-PET). The results of this work may identify important mechanisms through which inflammation increases CV risk in RA patients, and thereby determine new markers for risk assessment and specific targets for intervention.

描述（由申请人提供）：心血管疾病（CVD）是类风湿性关节炎（RA）患者的主要杀手，与普通人群相比，RA患者的心肌梗死风险增加2-3倍。传统的心血管（CV）危险因素本身不能准确预测RA患者的CVD，因此缺乏足够的一级预防策略。活动性RA的全身炎症与RA患者的CV风险密切相关，但炎症增加CV发病率和死亡率的机制尚不清楚。高密度脂蛋白（HDL）是一种抗动脉粥样硬化分子，通过促进胆固醇流出和防止低密度脂蛋白（LDL）氧化来调节全身炎症。我们以前已经证明，高密度脂蛋白功能受损，并显着相关的疾病活动和全身炎症，在RA患者。我们进一步表明，活动性RA导致HDL的氧化和蛋白质变化，导致HDL功能障碍。氧化型低密度脂蛋白（ox-LDL）通过关节滑膜中凝集素样ox-LDL受体1（LOX- 1）的信号传导直接参与RA的发病机制。我们的初步研究结果表明，通过增加HDL的能力，防止氧化LDL的HDL功能的调制与关节炎活动的改善。我们假设HDL功能的调节代表了一种新的途径，通过这种途径可以降低RA患者的关节炎活动性并改善CV风险。我们将在两个具体目标下检验我们的假设。在目标1中，我们将评估是否使用HDL模拟肽调节HDL功能可以减少最近建立的RA小鼠模型中的动脉粥样硬化和关节炎症。我们还将通过对氧磷酶1（PON 1）基因缺失和过表达来调节HDL功能，以评估对该模型中关节炎活动和动脉粥样硬化的影响。在目标2中，我们将使用HDL功能体外测定和靶向HDL蛋白质组学和脂质组学，在一个仔细表征的200多例RA患者的前瞻性队列中确定异常HDL功能是否有助于增加CV风险。CV风险将通过3年随访期间颈动脉粥样硬化的进展和使用氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）的颈动脉斑块炎症进行评估。这项工作的结果可能会确定炎症增加RA患者CV风险的重要机制，从而确定风险评估的新标志物和干预的具体目标。