Marie Octave, Laurence Pirotton, Emma de Cartier d'Yves, Alice Marino, Jérôme Ambroise, Martin Giera, Bruno Guigas, Audrey Ginion, Valentine Robaux, Marijke J E Kuijpers, Constance C F M J Baaten, Johan W M Heemskerk, Zoltan Nagy, Yotis A Senis, Davide Brusa, Caroline Bouzin, Luc Bertrand, Christophe Beauloye, Sandrine Horman
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引用次数: 0
Abstract
This study uncovers the pivotal role of acetyl-CoA carboxylase 1 (ACC1) in regulating platelet lipid composition, bioenergetics, activation, and thrombus formation, as demonstrated using a targeted GPIbα-Cre+/- mouse model. By comparing platelet-specific ACC1 knockout mice (pKO; GPIbα-Cre+/- x ACC1flx/flx) with both GPIbα-Cre+/- and ACC1flx/flx control groups, we showed that ACC1 deficiency profoundly reshaped the platelet phospholipidome. Specifically, ACC1 deletion led to decreased levels of arachidonic acid-containing phosphatidylethanolamine plasmalogens, thereby limiting thromboxane A2 synthesis, dense granule secretion, and platelet activation upon agonist stimulation. Bioenergetic analysis of ACC1-deficient platelets revealed reduced glycolytic activity, potentially worsening their activation defects. Notably, ACC1 deficiency also enhanced the mitochondrial reserve respiratory capacity, without altering basal respiration or ATP turnover. This increased reserve respiratory capacity correlated with reduced phosphatidylserine exposure, suggesting lower procoagulant activity. Importantly, we showed that ACC1 deficiency impaired thrombus formation without compromising hemostasis. Together, these findings identified ACC1 as a critical regulator of platelet function and highlighted its potential as a target for innovative anti-thrombotic therapies.
这项研究揭示了乙酰辅酶a羧化酶1 (ACC1)在调节血小板脂质组成、生物能量学、激活和血栓形成中的关键作用,并通过靶向GPIbα-Cre+/-小鼠模型证明了这一点。通过比较血小板特异性ACC1敲除小鼠(pKO;GPIbα-Cre+/- x ACC1flx/flx)与GPIbα-Cre+/-和ACC1flx/flx对照组相比,我们发现ACC1缺陷深刻地重塑了血小板磷脂组。具体来说,ACC1缺失导致含有花生四烯酸的磷脂酰乙醇胺浆磷脂原水平降低,从而限制了血栓素A2的合成、致密颗粒的分泌和激动剂刺激下的血小板活化。缺乏acc1的血小板的生物能量分析显示糖酵解活性降低,潜在地加重了它们的激活缺陷。值得注意的是,ACC1缺乏也增强了线粒体储备呼吸能力,而不改变基础呼吸或ATP的转换。这种增加的储备呼吸能力与磷脂酰丝氨酸暴露减少相关,表明促凝活性降低。重要的是,我们发现ACC1缺乏会损害血栓形成,但不会影响止血。总之,这些发现确定了ACC1是血小板功能的关键调节因子,并强调了其作为创新抗血栓治疗靶点的潜力。
期刊介绍:
Blood Advances, a semimonthly medical journal published by the American Society of Hematology, marks the first addition to the Blood family in 70 years. This peer-reviewed, online-only, open-access journal was launched under the leadership of founding editor-in-chief Robert Negrin, MD, from Stanford University Medical Center in Stanford, CA, with its inaugural issue released on November 29, 2016.
Blood Advances serves as an international platform for original articles detailing basic laboratory, translational, and clinical investigations in hematology. The journal comprehensively covers all aspects of hematology, including disorders of leukocytes (both benign and malignant), erythrocytes, platelets, hemostatic mechanisms, vascular biology, immunology, and hematologic oncology. Each article undergoes a rigorous peer-review process, with selection based on the originality of the findings, the high quality of the work presented, and the clarity of the presentation.