Differential thrombogenesis effects of EPA and DHA mediated by HDL

HDL 介导的 EPA 和 DHA 的差异血栓形成作用

• 批准号: 10660778
• 负责人: WENLIANG SONG
• 金额: $ 57.83万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-13 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660778
• 关键词: Address; Affect; Apolipoprotein A-I; Biological; Biological Markers; Blood Platelets; Blood coagulation; Cardiovascular system; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Consumption; Data; Development; Diet; Dietary Supplementation; Docosahexaenoic Acid n-3; Docosahexaenoic Acids; Dose; Dyslipidemias; Eicosapentaenoic Acid; Experimental Models; Fish Oils; Flow Cytometry; Head; Hemorrhage; High Density Lipoproteins; Human; Intervention; Investments; Knock-out; Knockout Mice; Laboratories; Leukocytes; Lipids; Lipoproteins; Mediating; Modeling; Modification; Mus; N-3 polyunsaturated fatty acid; Omega-3 Fatty Acids; Outcome; Patients; Phospholipids; Platelet Activation; Platelet aggregation; Population; Pre-Clinical Model; Principal Investigator; Production; Property; Randomized; Regimen; Reporting; Resources; Rest; Single-Blind Study; Supplementation; Testing; Therapeutic Effect; Thrombelastography; Thrombosis; Thromboxanes; Triglycerides; Whole Blood; cardiometabolic risk; cardioprotection; cardiovascular risk factor; combat; design; eicosanoid metabolism; epidemiology study; experimental study; head-to-head comparison; healthy volunteer; human subject; in vivo; insight; lipid mediator; marine; mouse model; novel therapeutics; outcome disparities; particle; platelet function; reconstitution; targeted treatment; thrombogenesis; thrombotic; urinary

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.

项目摘要 流行病学研究表明，omega-3多不饱和脂肪酸（N-3 PUFAS）的消费 源自鱼油，主要由eicosapentaenoic酸（EPA; 20：5 n-3）和Docosahexaenoic酸组成 （DHA; 22：6 n-3）与较低的心血管风险有关。但是，针对的介入临床试验 通过补充N-3 PUFA来减少心血管事件的结果不一致。这 N-3 PUFA对心血管风险的益处的机制仍未完全了解。 越来越多的证据表明，除了降低甘油三酸酯外，N-3的甘油三酸酯无关效应 PUFA还为他们的心血管益处做出了贡献。 EPA和DHA的差异效应也很可能 有助于不一致的临床结果。 EPA和EPA生物学作用的正面比较 迫切需要在相关人群中的DHA。根据我们的初步数据，我们假设EPA和 DHA对动脉粥样异常血症患者的血栓形成具有不同的影响，该患者介导 HDL粒子函数的修改。我们提出了比较生物学的概念验证临床研究 效果，尤其是血栓形成和抗血小板效应，对EPA和DHA的足够剂量前面 在动脉粥样硬化血脂血症受试者中头部。我们还将检查HDL颗粒如何介导的机制 这些抗血栓形成效应。特定目标1：检验EPA和DHA差异影响血小板的假设 动脉粥样硬化血脂血症受试者的体内激活和血栓形成。具有动脉粥样硬化的人类受试者 血脂血症将随机补充饮食中的四克EPA或DHA N-3 PUFA 一种单叶的时尚八个星期。基线和补充后，各种标记 将评估血栓形成。特定目的2：检验N-3 PUFAS对的假设 血小板是由HDL粒子函数的调节介导的。在基线和N-3 PUFA之后 将分别分析补充，HDL颗粒组成和HDL功能。我们将进一步测试 我们的假设在HDL缺陷小鼠模型中是机械的。 HDL依赖性生物活性脂质产生将 在人类和小鼠研究中都有特征。这些研究将洞悉新的范式 了解N-3 Pufas的令人困惑的临床证据，并最终可能导致新颖的发展 抗击心脏代谢风险的疗法。