Differential thrombogenesis effects of EPA and DHA mediated by HDL

项目摘要 流行病学研究表明，欧米茄-3多不饱和脂肪酸(n-3 PUFA)的摄入量 来源于鱼油，主要由二十碳五烯酸(EPA；20：5n-3)和二十二碳六烯酸组成 (DHA；22：6n-3)，与较低的心血管风险相关。然而，介入性临床试验旨在 通过补充n-3多不饱和脂肪酸来减少心血管事件产生了不一致的结果。这个 N-3多不饱和脂肪酸对心血管风险的益处机制仍不完全清楚。 越来越多的证据表明，除了降低甘油三酯外，n-3的非甘油三酯依赖的作用 多不饱和脂肪酸还有助于它们的心血管益处。很可能EPA和DHA的不同影响也 导致临床结果不一致。EPA和EPA生物效应的正面比较 迫切需要相关人群的DHA。根据我们的初步数据，我们假设环保局和 DHA对动脉粥样硬化性血脂异常患者血栓形成的不同影响 高密度脂蛋白颗粒函数的修饰。我们提出了一项概念验证临床研究，比较了 适当剂量的EPA和DHA的作用，特别是血栓形成和抗血小板作用 致动脉粥样硬化性血脂异常患者的头部。我们还将研究高密度脂蛋白颗粒如何调节的机制 这些抗血栓作用。特异性目的1：验证EPA和DHA对血小板有不同影响的假说 致动脉粥样硬化性血脂异常患者体内的活化和血栓形成。致动脉粥样硬化的人体受试者 血脂异常将被随机分配到饮食补充剂中，添加4克EPA或DHA n-3PUFAs 八周的单盲时尚。在基线和补充后，各种标志物 血栓形成情况将进行评估。具体目标2：检验n-3多不饱和脂肪酸对 血小板受高密度脂蛋白颗粒功能的调节。在基线和发布n-3多不饱和脂肪酸 补充、高密度脂蛋白颗粒组成和高密度脂蛋白功能将分别进行分析。我们将进一步测试 我们的假设是在高密度脂蛋白缺乏的小鼠模型中机械地进行的。依赖于高密度脂蛋白的生物活性脂肪的产生将 在人类和小鼠研究中都具有特征。这些研究将提供对一种新的 了解n-3多不饱和脂肪酸令人费解的临床证据，并最终可能导致新的 对抗心脏代谢风险的治疗方法。

Project Summary Epidemiological studies suggest that the consumption of omega-3 polyunsaturated fatty acids (n-3 PUFAs) derived from fish oil, mainly consisting of eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3), is associated with lower cardiovascular risk. However, interventional clinical trials aimed at reducing cardiovascular incidents by supplementation with n-3 PUFAs have yielded inconsistent results. The mechanisms responsible for the benefit of n-3 PUFAs on cardiovascular risk are still not completely understood. Mounting evidence suggests that in addition to lowering triglycerides, the triglyceride-independent effects of n-3 PUFAs also contribute to their cardiovascular benefits. It is likely that differential effects of EPA and DHA also contribute to the inconsistent clinical results. A head-to-head comparison of the biological effects of EPA and DHA in a relevant population is urgently required. Based on our preliminary data, we hypothesize that EPA and DHA have differential effects on thrombogenesis in patients with atherogenic dyslipidemia that are mediated by the modification of HDL particle function. We propose a proof-of-concept clinical study comparing the biological effects, particularly the thrombogenesis and antiplatelet effects, of an adequate dose of EPA and DHA head-to- head in atherogenic dyslipidemia subjects. We will also examine the mechanism of how HDL particles mediate these antithrombotic effects. Specific Aim1: To test the hypothesis that EPA and DHA differentially affect platelet activation and thrombosis in vivo in subjects with atherogenic dyslipidemia. Human subjects with atherogenic dyslipidemia will be randomized to dietary supplementation with four grams of either EPA or DHA n-3 PUFAs in a single-blinded fashion for eight weeks. At baseline and after the supplementation, various markers of thrombogenesis will be assessed. Specific Aim 2: To test the hypothesis that the effects of n-3 PUFAs on platelets are mediated by the modulation of HDL particle function. At baseline and post n-3 PUFA supplementation, HDL particle composition and HDL functions will be analyzed, respectively. We will further test our hypothesis mechanistically in an HDL-deficient mouse model. HDL-dependent bioactive lipid production will be characterized in both human and mouse studies. These studies will provide insight into a new paradigm of understanding the puzzling clinical evidence of n-3 PUFAs and may ultimately lead to the development of novel therapies to combat cardiometabolic risk.