VAS2870 and VAS3947 attenuate platelet activation and thrombus formation via a NOX-independent pathway downstream of PKC
VAS2870 and VAS3947 attenuate platelet activation and thrombus formation via a NOX-independent pathway downstream of PKC
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DOI：
10.1038/s41598-019-55189-5
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发表时间：
2019-12-11
影响因子：
4.6
通讯作者：
Lin, Kuan Hung
中科院分区：
文献类型：
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作者：
Lu, Wan Jung;Li, Jiun Yi;Lin, Kuan Hung
NADPH氧化酶（NOX）参与多种生理和病理过程，例如血小板活化和炎症。有趣的是，我们发现泛NOX抑制剂VAS化合物（VAS2870及其类似物VAS3947）发挥了高效的抗血小板作用。与 VAS 化合物不同，用 ML171、GSK2795039 和 GKT136901/GKT137831 治疗同时抑制 NOX1、2 和 4 不会影响凝血酶和 U46619 诱导的血小板聚集。这些发现表明 VAS 化合物可能通过不依赖 NOX 的方式抑制血小板聚集。因此，我们的目的是研究 VAS 化合物的详细抗血小板机制。数据显示，VAS 化合物可能通过阻断 PKC 下游信号传导（包括 IKK beta 和 p38 MAPK）阻断各种激动剂诱导的血小板聚集，最终减少血小板颗粒释放、钙动员和 GPIIbIIIa 激活。此外，VAS 化合物还能抑制胶原蛋白和凝血酶诱导的小鼠血小板聚集。体内研究还表明，VAS 化合物可以延迟血栓形成，而不影响正常止血。这项研究首次证明，除了抑制 NOX 活性外，VAS 化合物还可以通过 PKC 下游的 NOX 独立途径减少血小板活化和血栓形成。这些发现还表明，VAS 化合物可能是治疗心血管疾病患者的安全且潜在的治疗剂。
NADPH oxidase (NOX) enzymes are involved in a various physiological and pathological processes such as platelet activation and inflammation. Interestingly, we found that the pan-NOX inhibitors VAS compounds (VAS2870 and its analog VAS3947) exerted a highly potent antiplatelet effect. Unlike VAS compounds, concurrent inhibition of NOX1, 2, and 4 by treatment with ML171, GSK2795039, and GKT136901/GKT137831 did not affect thrombin and U46619-induced platelet aggregation. These findings suggest that VAS compounds may inhibit platelet aggregation via a NOX-independent manner. Thus, we aimed to investigate the detailed antiplatelet mechanisms of VAS compounds. The data revealed that VAS compounds blocked various agonist-induced platelet aggregation, possibly via blocking PKC downstream signaling, including IKK beta and p38 MAPK, eventually reducing platelet granule release, calcium mobilization, and GPIIbIIIa activation. In addition, VAS compounds inhibited mouse platelet aggregation-induced by collagen and thrombin. The in vivo study also showed that VAS compounds delayed thrombus formation without affecting normal hemostasis. This study is the first to demonstrate that, in addition to inhibiting NOX activity, VAS compounds reduced platelet activation and thrombus formation through a NOX-independent pathway downstream of PKC. These findings also indicate that VAS compounds may be safe and potentially therapeutic agents for treating patients with cardiovascular diseases.