糖库去氧胆酸(GUDCA)因其调节脂质稳态并为各种代谢紊乱提供益处的能力而被公认。然而,GUDCA对动脉血栓事件的影响仍未被研究.这项研究的目的是检查GUDCA对血栓形成的影响并阐明其潜在机制。
■收集来自具有动脉血栓形成事件的患者和饮食诱导的肥胖小鼠的血浆样品以使用质谱法测定GUDCA浓度。进行了多种体内鼠血栓形成模型和体外血小板功能测定,以全面评估GUDCA的抗血栓作用。此外,我们进行了脂质组学分析,以确定GUDCA治疗后血小板内脂质成分的改变.
■在动脉血栓事件患者中,血浆GUDCA水平显著降低,并且在饮食诱导的肥胖小鼠中,与血栓倾向呈负相关。GUDCA对血小板反应性表现出突出的抑制作用,如血小板活化的减弱所证明,分泌,聚合,传播,回缩(P<0.05)。在体内,GUDCA给药稳健地缓解血栓形成(P<0.05)而不影响止血。机械上,GUDCA抑制DGK(二酰甘油激酶)活性,导致磷脂酸介导的信号通路下调。相反,补充磷脂酸足以消除GUDCA的抗血栓形成作用。更重要的是,长期口服GUDCA可使增强的DGK活性正常化,从而显著减轻饮食诱导的肥胖小鼠的血小板高反应性以及增加的血栓形成倾向(P<0.05)。
■我们的研究暗示GUDCA通过抑制DGK活性降低血小板高反应性并改善血栓形成倾向,这是动脉血栓形成事件的潜在有效的预防方法和有希望的治疗剂。
UNASSIGNED: Glycoursodeoxycholic acid (GUDCA) has been acknowledged for its ability to regulate lipid homeostasis and provide benefits for various metabolic disorders. However, the impact of GUDCA on arterial thrombotic events remains unexplored. The objective of this study is to examine the effects of GUDCA on thrombogenesis and elucidate its underlying mechanisms.
UNASSIGNED: Plasma samples from patients with arterial thrombotic events and diet-induced obese mice were collected to determine the GUDCA concentrations using mass spectrometry. Multiple in vivo murine thrombosis models and in vitro platelet functional assays were conducted to comprehensively evaluate the antithrombotic effects of GUDCA. Moreover, lipidomic analysis was performed to identify the alterations of intraplatelet lipid components following GUDCA treatment.
UNASSIGNED: Plasma GUDCA level was significantly decreased in patients with arterial thrombotic events and negatively correlated with thrombotic propensity in diet-induced obese mice. GUDCA exhibited prominent suppressing effects on platelet reactivity as evidenced by the attenuation of platelet activation, secretion, aggregation, spreading, and retraction (P<0.05). In vivo, GUDCA administration robustly alleviated thrombogenesis (P<0.05) without affecting hemostasis. Mechanistically, GUDCA inhibited DGK (diacylglycerol kinase) activity, leading to the downregulation of the phosphatidic acid-mediated signaling pathway. Conversely, phosphatidic acid supplementation was sufficient to abolish the antithrombotic effects of GUDCA. More importantly, long-term oral administration of GUDCA normalized the enhanced DGK activity, thereby remarkably alleviating the platelet hyperreactivity as well as the heightened thrombotic tendency in diet-induced obese mice (P<0.05).
UNASSIGNED: Our study implicated that GUDCA reduces platelet hyperreactivity and improves thrombotic propensity by inhibiting DGKs activity, which is a potentially effective prophylactic approach and promising therapeutic agent for arterial thrombotic events.