【摘要】：目的:探討細胞外信號調(diào)節(jié)激酶5(ERK5)對體外血小板聚集及在體血栓的影響及機制。方法:采用Western blot對人血小板中ERK5的表達及其在血小板活化后的磷酸化水平進行檢測;采用血小板聚集儀檢測ERK5特異性抑制劑XMD8-92對血小板聚集及致密顆粒釋放的影響;采用Fe Cl3頸動脈血栓模型檢測ERK5對在體血栓的影響;采用Western blot檢測XMD8-92對蛋白激酶B(Akt)和人第10號染色體缺失的磷酸酶及張力蛋白同源蛋白(PTEN)磷酸化的影響。結(jié)果:人血小板中存在ERK5的穩(wěn)定表達,其磷酸化水平在血小板活化后顯著升高(P0.05)。XMD8-92可抑制多種血小板激活劑引起的血小板聚集和致密顆粒釋放(P0.05)。Western blot結(jié)果表明,XMD8-92可通過下調(diào)PTEN Ser370位點磷酸化而增強PTEN的活性,從而抑制Akt的磷酸化,這種抑制效果也通過血小板特異PTEN基因敲除小鼠得到了驗證。在體血栓研究表明,XMD8-92經(jīng)尾靜脈給藥,可顯著延長小鼠第一次頸動脈血栓的形成時間。結(jié)論:ERK5可通過影響PTEN的磷酸化調(diào)節(jié)Akt的活化,進而影響到體外血小板的聚集和在體血栓的形成。
[Abstract]:Aim: to investigate the effect and mechanism of extracellular signal-regulated kinase 5 (ERK5) on platelet aggregation and thrombosis in vitro. Methods: the expression of ERK5 in human platelets and its phosphorylation after platelet activation were detected by Western blot, and the effects of XMD8-92, a specific inhibitor of ERK5, on platelet aggregation and release of dense granules were detected by platelet aggregator. The effect of ERK5 on thrombus in vivo was detected by Fe Cl3 carotid thrombosis model, and the effect of XMD8-92 on phosphorylation of protein kinase B (Akt), phosphatase and tensin homologous protein (PTEN) in human chromosome 10 was detected by Western blot. Results: there was a stable expression of ERK5 in human platelets. The phosphorylation level of XMD8-92 increased significantly after platelet activation (P0.05). XMD8-92 inhibited platelet aggregation and dense particle release induced by many platelet activators (P0.05). Western blot results showed that XMD8-92 could enhance the activity of PTEN by down-regulating phosphorylation of PTEN Ser370 sites. Thus, the phosphorylation of Akt was inhibited, which was also demonstrated by platelet specific PTEN knockout mice. In vivo thrombus studies showed that XMD8-92 could significantly prolong the formation time of the first carotid thrombosis in mice. Conclusion the activation of Akt can be regulated by the phosphorylation of PTEN, which may affect platelet aggregation in vitro and thrombosis in vivo.
【作者單位】： 復(fù)旦大學(xué)附屬華山醫(yī)院心內(nèi)科;
【基金】：國家自然科學(xué)基金資助項目(No.81270278) 上海市科委基金資助項目(No.16411965600)
【分類號】：R54

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