12-HETrE regulation of blood coagulation, hemostasis, and thrombosis

12-HETrE 对凝血、止血和血栓形成的调节

• 批准号: 10474068
• 负责人: MICHAEL Allan HOLINSTAT
• 金额: $ 2.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474068
• 关键词: Affinity; Antiplatelet Drugs; Atherosclerosis; Blood Platelets; Blood coagulation; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Control Groups; Development; Disease; Event; Functional disorder; G-Protein-Coupled Receptors; Growth; Hemorrhage; Hemostatic function; High Density Lipoproteins; In Vitro; Investigation; LOX gene; Lead; Link; Mediating; Mediator of activation protein; Myocardial Infarction; Persons; Platelet Activation; Platelet aggregation; Play; Property; Prostaglandins I; Regulation; Risk; Role; Science; Stroke; Thrombosis; Thrombus; improved; in vivo; insight; nanocarrier; new therapeutic target; novel; platelet function; prevent; receptor

ABSTRACT Cardiovascular disease remains the main cause of death in the world, where 17.9 million people die every year. Platelet activation plays a primary role in the pathophysiology of cardiovascular disease, especially in atherosclerosis, and the inability to regulate platelet function leads to atherothrombotic events resulting in myocardial infarction and stroke. Currently available antiplatelet agents inhibit platelet aggregation at the great risk of bleeding. In our lab, we have identified the 12-LOX derived DGLA product, 12-HETrE, to potently inhibit platelet activation ex vivo and significantly prevented occlusive thrombus formation in vivo. Interestingly, due to its potent antithrombotic activities of 12-HETrE, investigations on its impact on normal hemostasis uncovered that there were no differences in bleeding occurrences between treated and control groups. Further studies revealed that 12-HETrE mediated its antiplatelet effects in part through the prostacyclin receptor and possibly through other G⍺s-linked G-protein-coupled receptors. These studies highlight the potential for further studies into the mechanisms of 12-HETrE which could lead to further discoveries of potential targets for the development of antiplatelet therapies that will not lead to unnecessary bleeding risks. Previously, we have identified bioactive synthetic high-density lipoprotein (sHDL) as a mediator of platelet activation, where it was internalized by platelets and inhibited platelet aggregation in vitro and inhibited thrombus growth in vivo. Therefore, in this present study we will be further investigating the mechanisms of 12-HETrE in combination with the sHDL nanocarriers in its interactions with platelets to prevent thrombosis. The successful completion of this present study will provide robust mechanistic insight into how sHDL is able to improve 12-HETrE's antiplatelet properties and where or not it will increase its affinity for the IP receptor.

摘要 心血管疾病仍然是世界上主要的死亡原因，每年有1790万人死亡。 年血小板活化在心血管疾病的病理生理学中起主要作用，特别是在 动脉粥样硬化和不能调节血小板功能导致动脉粥样硬化血栓形成事件， 心肌梗塞和中风。目前可用的抗血小板药物抑制血小板聚集在很大程度上 出血的风险。在我们的实验室中，我们已经鉴定了12-LOX衍生的DGLA产物，12-HETrE，以有效地抑制 离体血小板活化并显著防止体内闭塞性血栓形成。有趣的是，由于 12-HETrE的强效抗血栓形成活性，其对正常止血影响的研究发现， 治疗组和对照组之间的出血发生率无差异。进一步研究 表明12-HETrE部分通过前列环素受体介导其抗血小板作用， 通过其他G蛋白连接的G蛋白偶联受体这些研究突出了进一步研究的潜力 12-HETrE的机制，这可能导致进一步发现潜在的目标， 开发不会导致不必要出血风险的抗血小板治疗。此前，我们有 确定了生物活性合成高密度脂蛋白（sHDL）作为血小板活化的介质， 通过血小板内化并在体外抑制血小板聚集和在体内抑制血栓生长。 因此，在本研究中，我们将进一步研究12-HETrE联合 与sHDL纳米载体在其与血小板的相互作用，以防止血栓形成。圆满完成 本研究的结果将为sHDL如何能够改善12-HETrE提供可靠的机制见解 抗血小板特性以及是否增加其对IP受体的亲和力。