Aspirin-triggered Specialized Pro-resolving Mediators in Increasing Weight and Atherosclerotic Cardiovascular Disease

项目摘要 每日低剂量阿司匹林是预防心血管（CV）事件的常规处方药，尽管以下方面的数据相互矛盾： 它的功效，尤其是随着体重的增加。虽然阿司匹林旨在抑制血小板聚集，但它具有 在降低受体重影响的CV风险方面可能重要的其他效应。 肥胖和动脉粥样硬化的特征都是慢性、低度炎症， 旨在减少炎症的治疗可改善CV结局。炎症的解决需要 专门的促分解脂质介质（SPM）。几种SPM及其前体被称为“阿司匹林- 触发”（AT），因为它们的产生在乙酰化考克斯-2的存在下被刺激。我们和其他人已经 显示AT-SPM，包括15-表-脂氧素A4（15 R-LXA 4），在肥胖者的血液和组织中减少， 人类临床前模型已经确定AT-SPM抑制动脉粥样硬化进展， 斑块稳定作用。小的横断面人类队列显示AT-SPM与 与动脉粥样硬化的严重程度相关，但与前瞻性CV结局的潜在相关性尚未得到检验。 最大的阿司匹林试验荟萃分析显示，低剂量阿司匹林可有效降低主要 仅在体重<70 kg的受试者中发生不良CV事件（MACE），而剂量> 300 mg显示出增加 随着体重的增加而增加。虽然建议解释这些发现，数据不完整的血小板 低剂量阿司匹林对考克斯-1的抑制作用与体重的增加尚无定论。因此，阿司匹林介导 血小板聚集和血栓形成功能的外在因素，如AT-SPM缺陷，可能介导 肥胖在心血管疾病中的作用，以及随着体重的增加，低剂量阿司匹林的益处减少。 我们的中心假设是AT-SPM水平降低导致CV风险过高和CV恶化 低剂量阿司匹林治疗的结果。在我们的第一个目标中，我们将测试低剂量和常规剂量阿司匹林的作用 在广泛的体重范围内，使用AT-SPM方案对人体的AT-SPM水平和细胞功能进行了研究。 随机安慰剂对照交叉试验。我们将测量脂质介质，包括血栓素， 白细胞三烯和SPM，在血清和中性粒细胞治疗前后与阿司匹林。我们亦会评估 细胞炎症指标，包括血小板活性、血小板-白细胞聚集体和白细胞 SPM受体的表面表达。在目标2中，我们将评估15 R-LXA 4对MACE的预测能力， 患有稳定缺血性心脏病的人服用阿司匹林。使用嵌套病例对照设计，我们将评估 ISCHEMIA随机对照试验中402例受试者的血清SPM谱，并评价 SPM曲线预测这些受试者的CV结局。我们还将评估体重的中介作用 15 R-LXA 4水平。 这项工作将评估阿司匹林在CVD治疗中的新机制作用，与血栓形成分开， 这可能解释了体重增加导致的更糟糕的结果。

Project Summary Daily low-dose aspirin is routinely prescribed to prevent cardiovascular (CV) events, despite conflicting data on its efficacy, especially with increasing body weight. While intended to inhibit platelet aggregation, aspirin has other effects that may be important in reducing CV risk that are influenced by body weight. Obesity and atherosclerosis are both characterized by chronic, low-grade inflammation and some treatments aimed at reducing inflammation improve CV outcomes. The resolution of inflammation requires specialized pro-resolving lipid mediators (SPMs). Several SPMs and their precursors are termed “aspirin- triggered” (AT), as their production is stimulated in the presence of acetylated COX-2. We and others have shown that AT-SPMs, including 15-epi-lipoxin A4 (15R-LXA4), are reduced in blood and tissues from obese humans. Pre-clinical models have established that AT-SPMs inhibit atherosclerosis progression and have plaque stabilizing effects. Small cross-sectional human cohorts have shown AT-SPMs inversely associated with severity of atherosclerosis, but a potential association with prospective CV outcomes has not been tested. The largest meta-analysis of aspirin trials showed that low-dose aspirin was effective at reducing major adverse CV events (MACE) only in those weighing <70kg, whereas doses >300mg exhibited increasing efficacy as body weight increased. While suggested to explain these findings, data on incomplete platelet COX-1 inhibition from low-dose aspirin with increasing body weight are inconclusive. Thus, aspirin-mediated factors extrinsic to platelet function in aggregation and thrombosis, such as deficient AT-SPMs, may mediate obesity’s role in CVD and reduced benefit from low-dose aspirin with increasing body weight. Our central hypothesis is that reduced levels of AT-SPMs contribute to excess CV risk and worse CV outcomes with low-dose aspirin therapy. In our first Aim, we will test the effects of low- and regular-dose aspirin regimens on AT-SPM levels and cellular function in humans across a wide range of body weights using a randomized, placebo-controlled, crossover trial. We will measure lipid mediators, including thromboxanes, leukotrienes, and SPMs, in serum and neutrophils before and after treatment with aspirin. We will also assess measures of cellular inflammation including platelet activity, platelet-leukocyte aggregates, and leukocyte surface expression of SPM receptors. In Aim 2, we will assess a predictive capacity of 15R-LXA4 for MACE in persons with stable ischemic heart disease taking aspirin. Using a nested case-control design, we will assess serum SPM profiles in 402 subjects in the ISCHEMIA randomized controlled trial and evaluate the capacity of SPM profiles to predict CV outcomes in these subjects. We will also assess a mediating effect of body weight on 15R-LXA4 levels. This work will evaluate a novel mechanistic role for aspirin in CVD treatment, separate from thrombosis, that may explain worse outcomes with increasing body weight.