Mechanisms Linking Joint Inflammation and Atherosclerosis in Rheumatoid Arthritis

描述(申请人提供)：心血管疾病(CVD)是类风湿关节炎(RA)患者的头号杀手，与普通人群相比，他们患心肌梗死的风险增加了2-3倍。仅有传统的心血管危险因素并不能准确预测RA患者的心血管疾病，因此缺乏足够的初级预防策略。活动期RA的全身性炎症与RA患者的心血管风险密切相关，但炎症增加心血管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的分子，通过促进胆固醇外流和防止低密度脂蛋白(LDL)的氧化来调节全身炎症。我们以前已经证明，在RA患者中，高密度脂蛋白功能受损，并与疾病活动性和全身炎症显著相关。我们进一步证明，活动性RA导致高密度脂蛋白的氧化和蛋白质变化，从而导致高密度脂蛋白功能障碍。氧化低密度脂蛋白(OX-LDL)通过关节滑膜凝集素样氧化低密度脂蛋白受体1(LOX-1)传递信号，直接参与RA的发病。我们的初步结果表明，通过增加高密度脂蛋白防止低密度脂蛋白氧化的能力来调节高密度脂蛋白的功能与关节炎活动的改善有关。我们假设，高密度脂蛋白功能的调节代表了一种新的途径，通过它既可以减少关节炎活动，又可以改善类风湿关节炎患者的心血管风险。我们将在两个具体目标下测试我们的假设。在目标1中，我们将评估使用高密度脂蛋白模拟肽调节高密度脂蛋白功能是否可以减少最近建立的类风湿关节炎小鼠模型的动脉粥样硬化和关节炎症。我们还将通过对氧磷酶1(PON1)基因的缺失和过表达来调节高密度脂蛋白的功能，以评估在该模型中对关节炎活动和动脉粥样硬化的影响。在目标2中，我们将使用体外高密度脂蛋白功能分析和靶向高密度脂蛋白组学和脂类组学的方法，在一个经过仔细描述的、具有前瞻性的超过200名RA患者队列中，确定高密度脂蛋白功能异常是否导致心血管风险增加。心血管风险将通过三年随访的颈动脉粥样硬化进展和使用正电子发射断层扫描(FDG-PET)的颈动脉斑块炎症来评估。这项工作的结果可能确定炎症增加RA患者心血管风险的重要机制，从而确定新的风险评估标记物和干预的特定靶点。

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.