Pharmacological inhibition of Septins with Forchlorfenuron attenuates thrombus formation in experimental thrombotic mice models with modulating multiple signaling pathways in platelets,Journal of Advanced Research

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Pharmacological inhibition of Septins with Forchlorfenuron attenuates thrombus formation in experimental thrombotic mice models with modulating multiple signaling pathways in platelets
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-08-05 , DOI: 10.1016/j.jare.2024.08.006
Zhen Hao ₁ , Minghui Yan ₁ , Reyisha Tuerhong ₁ , Luying Zhang ₁ , Zhen Zhang ₁ , Habib Alam ₁ , Jun Wu ₂ , Yuanhua Qin ₁ , Feng Zhao ₁ , Lei Shi ₁

Affiliation

Introduction

The Septin family of cytoskeletal proteins is abundant in platelets. When these proteins are functionally blocked using the compound forchlorfenuron (FCF), it hampers the normal activation processes of purified human platelets.

Objectives

To evaluate the in vivo effects of FCF on physiological haemostasis and pathological thrombosis in mice and to investigate possible molecular mechanisms.

Methods

The impact of FCF on haemorrhage risk in the brain, liver, and tail of mice was investigated. Using several experimental models, thrombus development in the lung, mesenteric arteries, and postcava was studied. Functional assays were performed on mice and human platelets, both with and without FCF pretreatment. These tests included aggregation, granule release, ROS production, integrin αIIbβ3 activation, cytoskeletal remodeling imaging, and clot retraction.

Results

Neither oral nor intravenous administration of FCF showed any apparent impairment of haemostasis in the tissues studied, but only later administration resulted in a significant reduction in thrombus formation in different mice vessel types. FCF generally inhibited agonist-induced platelet aggregation, degranulation, ROS burst, morphological expansion on the fibrinogen matrix with completely disordered dynamic organizations of the cytoskeleton for septin, tubulin and actin. In addition, FCF was found to antagonise agonist-induced dephosphorylation of VASP (Ser239) and PI3K/AKT and ERK1/2 phosphorylation.

Conclusion

FCF showed preferences in attenuating pathological thrombus formation, apart from physiological haemostasis, with possible mechanisms to prevent cytoskeletal remodelling and signal transduction of AKT, ERK1/2 and VASP signalling pathways, suggesting that Septin may serve as a promising target for the prevention and treatment of thrombotic diseases.

中文翻译：

用 Forchlorfenuron 对 Septins 的药理学抑制可减轻调节血小板中多种信号通路的实验血栓小鼠模型中的血栓形成

介绍

细胞骨架蛋白的 Septin 家族在血小板中含量丰富。当这些蛋白质使用化合物氯苯脲（FCF）进行功能阻断时，它会阻碍纯化的人血小板的正常激活过程。

目标

评价 FCF 对小鼠生理性止血和病理性血栓形成的体内影响，并探讨可能的分子机制。

方法

研究了 FCF 对小鼠脑、肝和尾部出血风险的影响。使用几种实验模型，研究了肺、肠系膜动脉和腔后血栓的形成。对小鼠和人血小板进行功能测定，有和没有 FCF 预处理。这些测试包括聚集、颗粒释放、ROS 产生、整合素 αIIbβ3 激活、细胞骨架重塑成像和凝块回缩。

结果

口服和静脉内给药 FCF 均未显示所研究组织中任何明显的止血损伤，但只有后来的给药才导致不同小鼠血管类型中血栓形成的显着减少。FCF 通常抑制激动剂诱导的血小板聚集、脱颗粒、ROS 爆发、纤维蛋白原基质上的形态学扩增，以及 septin 、 tubulin 和 actin 的细胞骨架动态组织完全无序。此外，发现 FCF 可拮抗激动剂诱导的 VASP （Ser239）和 PI3K/AKT 去磷酸化以及 ERK1/2 磷酸化。