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Adiponectin receptor agonist AdipoRon modulates human and mouse platelet function
Acta Pharmacologica Sinica ( IF 8.2 ) Pub Date : 2022-08-02 , DOI: 10.1038/s41401-022-00943-1
Xiang-Hui Zhou 1, 2 , Zhi-Peng Cheng 1, 2 , Meng Lu 3 , Wen-Yi Lin 1, 2 , Li-Li Luo 1, 2 , Zhang-Yin Ming 3, 4 , Yu Hu 1, 2, 5
Affiliation  

Adiponectin, an adipokine secreted by adipocytes, has anti-atherosclerotic and antithrombotic activities. AdipoRon is synthetic small molecule adiponectin receptor agonist. In this study, we investigated the effect of AdipoRon on platelet activation and thrombus formation. Washed human platelets were prepared from the peripheral blood of healthy donors. In a series of in vitro platelet functional assays, pre-treatment with AdipoRon (10, 20, 40 µg/mL) dose-dependently inhibited the aggregation, granule secretion and spreading of washed human platelets. We showed that AdipoRon (20, 40 µg/mL) significantly inhibited AMPK, Syk, PLCγ2, PI3K, Akt, p38-MAPK and ERK1/2 signalling pathways in washed human platelets. In addition, we demonstrated that the phosphorylation of CKII at Tyr255 was an important mechanism of the integrin αIIbβ3-mediated platelet activation. Meanwhile, AdipoR1 deficiency impaired the inhibitory effect of AdipoRon on mouse platelets. In ferric chloride-induced carotid injury model, injection of AdipoRon (5 or 12.5 mg/kg, iv) significantly attenuated arterial thrombosis. In conclusion, AdipoRon attenuates platelet function via the AdipoR1/AMPK/CKII/PI3K/AKT signalling pathways, while exerting a protective effect against arterial thrombosis. This study offers new insights into the fields of cardiovascular disease and antiplatelet drug discovery.

Schematic model of AdipoRon regulating platelet activation. (BioRender.com)



中文翻译:

脂联素受体激动剂 AdipoRon 调节人和小鼠血小板功能

脂联素是由脂肪细胞分泌的一种脂肪因子,具有抗动脉粥样硬化和抗血栓形成活性。AdipoRon 是合成的小分子脂联素受体激动剂。在这项研究中,我们研究了 AdipoRon 对血小板活化和血栓形成的影响。从健康供体的外周血中制备洗涤过的人血小板。在一系列体外血小板功能测定中,用 AdipoRon(10、20、40 µg/mL)预处理会剂量依赖性地抑制洗涤过的人血小板的聚集、颗粒分泌和扩散。我们发现 AdipoRon (20, 40 µg/mL) 显着抑制洗涤过的人血小板中的 AMPK、Syk、PLCγ2、PI3K、Akt、p38-MAPK 和 ERK1/2 信号通路。此外,我们证明了 CKII 在 Tyr255 的磷酸化是整合素 αIIbβ3 介导的血小板激活的重要机制。同时,AdipoR1 缺陷削弱了 AdipoRon 对小鼠血小板的抑制作用。在氯化铁诱导的颈动脉损伤模型中,注射 AdipoRon(5 或 12.5 mg/kg,静脉注射)可显着减轻动脉血栓形成。总之,AdipoRon 通过 AdipoR1/AMPK/CKII/PI3K/AKT 信号通路减弱血小板功能,同时发挥抗动脉血栓形成的保护作用。这项研究为心血管疾病和抗血小板药物发现领域提供了新的见解。iv) 显着减弱动脉血栓形成。总之,AdipoRon 通过 AdipoR1/AMPK/CKII/PI3K/AKT 信号通路减弱血小板功能,同时发挥抗动脉血栓形成的保护作用。这项研究为心血管疾病和抗血小板药物发现领域提供了新的见解。iv) 显着减弱动脉血栓形成。总之,AdipoRon 通过 AdipoR1/AMPK/CKII/PI3K/AKT 信号通路减弱血小板功能,同时发挥抗动脉血栓形成的保护作用。这项研究为心血管疾病和抗血小板药物发现领域提供了新的见解。

AdipoRon 调节血小板活化的示意图。(BioRender.com)

更新日期:2022-08-02
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