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.

项目概要 流行病学研究表明，食用 omega-3 多不饱和脂肪酸 (n-3 PUFA) 源自鱼油，主要成分为二十碳五烯酸（EPA；20:5 n-3）和二十二碳六烯酸 （DHA；22:6 n-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 PUFA 来减少心血管事件的结果并不一致。这 n-3 PUFA 对心血管风险有益的机制尚不完全清楚。 越来越多的证据表明，除了降低甘油三酯之外，n-3 的独立于甘油三酯的作用 PUFA 还有助于心血管益处。 EPA 和 DHA 的不同作用也可能 导致临床结果不一致。 EPA 和 EPA 的生物效应的头对头比较 相关人群迫切需要 DHA。根据我们的初步数据，我们假设 EPA 和 DHA 对动脉粥样硬化性血脂异常患者的血栓形成有不同的影响，而动脉粥样硬化性血脂异常是由以下因素介导的： HDL粒子函数的修改。我们提出了一项概念验证临床研究，比较生物学 足够剂量的 EPA 和 DHA 的作用，特别是血栓形成和抗血小板作用 动脉粥样硬化血脂异常受试者的头部。我们还将研究 HDL 颗粒如何介导的机制 这些抗血栓作用。具体目标 1：检验 EPA 和 DHA 对血小板影响不同的假设 患有动脉粥样硬化血脂异常的受试者体内的激活和血栓形成。患有动脉粥样硬化的人类受试者 血脂异常患者将随机接受膳食补充剂，其中含有 4 克 EPA 或 DHA n-3 PUFA 为期八周的单盲时尚。在基线和补充后，各种标记物 将评估血栓形成。具体目标 2：检验 n-3 PUFA 对人体的影响这一假设 血小板是通过 HDL 颗粒功能的调节介导的。基线时和 n-3 PUFA 后 补充后，将分别分析HDL颗粒组成和HDL功能。我们将进一步测试 我们的假设是在 HDL 缺陷小鼠模型中实现的。 HDL 依赖性生物活性脂质的产生将 在人类和小鼠研究中进行表征。这些研究将提供对新范式的见解 了解 n-3 PUFA 令人困惑的临床证据，并可能最终导致新型药物的开发 对抗心脏代谢风险的疗法。