Wadding-Lee Caris A, Jay Megan, Jones Shannon M, Thompson Joel, Howatt Deborah A, Daugherty Alan, Mackman Nigel, Owens A Phillip
bioRxiv. 2024 Aug 6:2024.08.01.606266. doi: 10.1101/2024.08.01.606266.
Cardiovascular disease (CVD) is a significant burden globally and, despite current therapeutics, remains the leading cause of death. Platelet inhibitors are of interest in CVD treatment to reduce thrombus formation post-plaque rupture as well their contribution to inflammation throughout the progression of atherosclerosis. Protease activated receptor 4 (PAR4) is a receptor highly expressed by platelets, strongly activated by thrombin, and plays a vital role in platelet activation and aggregation. However, the role of PAR4.
Mice on a low-density lipoprotein receptor-deficient ( ) background were bred with deficient ( ) mice to create and cousin lines. Mice were fed high fat (42%) and cholesterol (0.2%) 'Western' diet for 12 weeks for all studies. Bone marrow transplant (BMT) studies were conducted by irradiating and mice with 550 rads (2x, 4 hours apart) and then repopulated with or bone marrow. To determine if the effects of thrombin were mediated solely by PAR4, the thrombin inhibitor dabigatran was added to the 'Western' diet. given dabigatran did not further decrease their atherosclerotic burden. Differences between apolipoprotein E deficient ( ) and platelets were assessed for changes in reactivity. We observed higher PAR4 abundance in arteries with atherosclerosis in human and mice versus healthy controls. PAR4 deficiency attenuated atherosclerosis in the aortic sinus and root versus proficient controls. BMT studies demonstrated this effect was due to hematopoietic cells, most likely platelets. PAR4 appeared to be acting independent of PAR1, as there werer no changes with addition of dabigatran to PAR4 deficient mice. platelets are hyperreactive compared to platelets.
Hematopoietic-derived PAR4, most likely platelets, plays a vital role in the development and progression of atherosclerosis. Specific targeting of PAR4 may be a potential therapeutic target for CVD.
Deficiency of protease-activated receptor 4 attenuates the development of diet-induced atherosclerosis in a mouse model. PAR4 deficiency in hematopoietic cells is atheroprotective. PAR4 deficiency accounts for the majority of thrombin-induced atherosclerosis in a mouse model. The examination of platelet-specific proteins and platelet activation should be carefully considered before using the or mouse models of atherosclerosis.
心血管疾病（CVD）是全球范围内的一项重大负担，尽管有当前的治疗方法，但它仍是主要的死亡原因。血小板抑制剂在CVD治疗中备受关注，可减少斑块破裂后的血栓形成以及它们在动脉粥样硬化整个进展过程中对炎症的影响。蛋白酶激活受体4（PAR4）是一种在血小板中高度表达的受体，被凝血酶强烈激活，并在血小板激活和聚集中起关键作用。然而，PAR4的作用。
将低密度脂蛋白受体缺陷（ ）背景的小鼠与 缺陷（ ）小鼠杂交，以创建 和 近亲品系。在所有研究中，给小鼠喂食高脂肪（42%）和胆固醇（0.2%）的“西方”饮食12周。通过用550拉德（分两次，间隔4小时）照射 和 小鼠，然后用 或 骨髓进行再填充，进行骨髓移植（BMT）研究。为了确定凝血酶的作用是否仅由PAR4介导，将凝血酶抑制剂达比加群添加到“西方”饮食中。给予达比加群的 并没有进一步降低其动脉粥样硬化负担。评估载脂蛋白E缺陷（ ）和 血小板之间反应性的变化。我们观察到，与健康对照相比，人和小鼠动脉粥样硬化动脉中PAR4丰度更高。与野生型对照相比，PAR4缺陷减轻了主动脉窦和根部的动脉粥样硬化。BMT研究表明，这种作用归因于造血细胞，很可能是血小板。PAR4似乎独立于PAR1起作用，因为向PAR4缺陷小鼠添加达比加群后没有变化。 血小板比 血小板反应性更高。
造血来源的PAR4，很可能是血小板，在动脉粥样硬化的发生和发展中起关键作用。PAR4的特异性靶向可能是CVD的一个潜在治疗靶点。
蛋白酶激活受体4缺陷可减轻 小鼠模型中饮食诱导的动脉粥样硬化的发展。造血细胞中的PAR4缺陷具有抗动脉粥样硬化作用。在 小鼠模型中，PAR4缺陷占凝血酶诱导的动脉粥样硬化的大部分。在使用 或 动脉粥样硬化小鼠模型之前，应仔细考虑对血小板特异性蛋白和血小板激活的检查。
