Humanin analogue, HNG, inhibits platelet activation and thrombus formation by stabilizing platelet microtubules
Humanin analogue, HNG, inhibits platelet activation and thrombus formation by stabilizing platelet microtubules
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护脑素类似物 HNG 通过稳定血小板微管来抑制血小板活化和血栓形成
DOI：
10.1111/jcmm.15151
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发表时间：
2020-04-01
影响因子：
5.3
通讯作者：
Zhu, Li
中科院分区：
文献类型：
--
作者：
Ren, Lijie;Li, Qing;Zhu, Li
HNG是抗阿尔茨海默病多肽-人素的高效突变体，已被证明对缺血再灌注(I/R)损伤具有保护作用。然而，与血小板活化相关的潜在机制仍不清楚。我们认为HNG对血小板功能和血栓形成有影响。在这项研究中，评估了流动条件下的血小板聚集、颗粒分泌、凝块回缩、整合素活化和黏附。在接受HNG或生理盐水的小鼠中，记录激光损伤所致的提睾肌动脉血栓形成、尾部出血时间和失血量。免疫荧光染色检测血小板微管解聚情况。结果显示，在流动条件下，HNG可抑制血小板聚集、P-选择素表达、ATP释放、α(IIb)β(3)活化和黏附。接受HNG治疗的小鼠虽然出血时间没有延长，但却减少了提睾肌动脉血栓的形成。此外，HNG显著抑制微管解聚，增强纤维蛋白原或微管解聚试剂诺可达唑刺激的微管蛋白乙酰化，并抑制胶原刺激的HDAC6下游AKT和ERK的磷酸化。因此，我们的结果证实了HNG可能通过微管乙酰化稳定血小板微管，从而在血小板功能和血栓形成中发挥新的作用。这些发现表明，HNG在心血管疾病的管理中具有潜在的好处。
HNG, a highly potent mutant of the anti-Alzheimer peptide-humanin, has been shown to protect against ischaemia-reperfusion (I/R) injury. However, the underlying mechanism related to platelet activation remains unknown. We proposed that HNG has an effect on platelet function and thrombus formation. In this study, platelet aggregation, granule secretion, clot retraction, integrin activation and adhesion under flow conditions were evaluated. In mice receiving HNG or saline, cremaster arterial thrombus formation induced by laser injury, tail bleeding time and blood loss were recorded. Platelet microtubule depolymerization was evaluated using immunofluorescence staining. Results showed that HNG inhibited platelet aggregation, P-selectin expression, ATP release, and alpha(IIb)beta(3) activation and adhesion under flow conditions. Mice receiving HNG had attenuated cremaster arterial thrombus formation, although the bleeding time was not prolonged. Moreover, HNG significantly inhibited microtubule depolymerization, enhanced tubulin acetylation in platelets stimulated by fibrinogen or microtubule depolymerization reagent, nocodazole, and inhibited AKT and ERK phosphorylation downstream of HDAC6 by collagen stimulation. Therefore, our results identified a novel role of HNG in platelet function and thrombus formation potentially through stabilizing platelet microtubules via tubulin acetylation. These findings suggest a potential benefit of HNG in the management of cardiovascular diseases.