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，摄入omega-3多不饱和脂肪酸（n-3 PUFA） 来源于鱼油，主要由二十碳五烯酸（EPA; 20：5 n-3）和二十二碳六烯酸组成 (DHA; 22：6 n-3），与较低的心血管风险相关。然而，干预性临床试验旨在 通过补充n-3 PUFA减少心血管事件产生了不一致的结果。的 负责n-3 PUFA对心血管风险的益处的机制仍然没有完全理解。 越来越多的证据表明，除了降低甘油三酯外，n-3的非甘油三酯依赖性作用 PUFA也有助于其心血管益处。很可能EPA和DHA的不同作用也 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对致动脉粥样硬化性血脂异常患者的血栓形成有不同的影响， HDL粒子功能的修饰。我们提出了一项概念验证临床研究， 效果，特别是血栓形成和抗血小板作用，足够剂量的EPA和DHA头对 致动脉粥样硬化性血脂异常受试者的头部。我们还将研究HDL颗粒如何介导 这些抗血栓作用。具体目标1：检验EPA和DHA对血小板的影响不同的假设 活化和血栓形成。致动脉粥样硬化的人类受试者 血脂异常者将被随机分配至4克EPA或DHA n-3 PUFA的膳食补充剂组， 单盲实验八周在基线和补充后， 将评估血栓形成。具体目的2：检验n-3 PUFA对以下假设的影响： 血小板通过HDL颗粒功能的调节来介导。基线和n-3后PUFA 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 我们的假设在HDL缺陷小鼠模型中的机制。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。这些研究将提供一个新的范式， 了解n-3 PUFA的令人困惑的临床证据，并可能最终导致新的开发。 治疗来对抗心脏代谢风险。