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

项目摘要 每天服用小剂量阿司匹林是预防心血管事件的常规处方，尽管关于 它的功效，特别是在体重增加的情况下。虽然阿司匹林旨在抑制血小板聚集，但它有 其他可能对降低受体重影响的心血管风险很重要的影响。 肥胖和动脉粥样硬化的特征都是慢性、低度炎症和一些 旨在减少炎症的治疗可以改善心血管疾病的结果。炎症的消退需要 专门化的促分解脂质介体(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COX-2的存在下被刺激。我们和其他人有 研究表明，肥胖者血液和组织中的AT-SPM，包括15-表脂蛋白A4(15R-LXA4)减少 人类。临床前模型已经证实，AT-SPM可以抑制动脉粥样硬化的进展，并具有 具有稳定斑块的作用。较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有关，但与预期心血管预后的潜在相关性尚未得到检验。 对阿司匹林试验进行的最大规模的荟萃分析表明，小剂量阿司匹林有效地降低了 不良心血管事件(MACE)仅在体重为70公斤的人中发生，而剂量为300毫克的人表现出增加的趋势 功效随着体重的增加而增加。虽然建议解释这些发现，但关于不完全血小板的数据 小剂量阿司匹林对COX-1的抑制作用随着体重的增加而增加，这是不确定的。因此，阿司匹林介导的 凝集和血栓形成中的血小板功能外在因素，如AT-SPM缺陷，可能起到调节作用 肥胖在心血管疾病中的作用以及小剂量阿司匹林的益处随着体重的增加而减少。 我们的中心假设是，AT-SPM水平降低会导致过度的心血管风险和更差的心血管 小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的阿司匹林的效果 对不同体重范围的人体AT-SPM水平和细胞功能的影响 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， 阿司匹林治疗前后血清和中性粒细胞中的白三烯和SPM。我们还将评估 包括血小板活性、血小板-白细胞聚集性和白细胞在内的细胞炎症指标 SPM受体的表面表达。在目标2中，我们将评估15R-LXA4对MACE的预测能力 病情稳定的缺血性心脏病患者服用阿司匹林。使用嵌套病例对照设计，我们将评估 脑缺血随机对照试验中402例受试者的血清SPM谱 SPM资料用于预测这些受试者的心血管事件结局。我们还将评估体重的中介效应。 在15R-LXA4水平上。 这项工作将评估阿司匹林在CVD治疗中的一种新的机制作用，将其与血栓形成分开， 这可能解释了体重增加会导致更糟糕的结果。

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.