解析热休克蛋白家族成员对血小板功能的重叠影响的药理学。
Pharmacologic dissection of the overlapping impact of heat shock protein family members on platelet function.
机构信息
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Center for Cancer Research, Confocal Microscopy Core Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
出版信息
J Thromb Haemost. 2020 May;18(5):1197-1209. doi: 10.1111/jth.14758. Epub 2020 Mar 30.
BACKGROUND
Platelets play a pivotal role in hemostasis, wound healing, and inflammation, and are thus implicated in a variety of diseases, including cancer. Platelet function is associated with release of granule content, cellular shape change, and upregulation of receptors that promote establishment of a thrombus and maintenance of hemostasis.
OBJECTIVES
The role of heat shock proteins (Hsps) in modulating platelet function has been studied for a number of years, but comparative roles of individual Hsps have not been thoroughly examined.
METHODS
We utilized a panel of specific inhibitors of Hsp40, Hsp70, Hsp90, and Grp94 (the endoplasmic reticulum homolog of Hsp90) to assess their impact on several aspects of platelet function.
RESULTS
Inhibition of each of the aforementioned Hsps reduced alpha granule release. In contrast, there was some selectivity in impacts on dense granule release. Thromboxane synthesis was impaired after exposure to inhibitors of Hsp40, Hsp90, and Grp94, but not after inhibition of Hsp70. Both expression of active glycoprotein IIb/IIIa (GPIIb/IIIa) and fibrinogen-induced platelet shape change were diminished by our inhibitors. In contrast, aggregation was selectively abrogated after inhibition of Hsp40 or Hsp90. Lastly, activated platelet-cancer cell interactions were reduced by inhibition of both Hsp70 and Grp94.
CONCLUSIONS
These data suggest the importance of Hsp networks in regulating platelet activity.
背景
血小板在止血、伤口愈合和炎症中起着关键作用，因此与多种疾病有关，包括癌症。血小板功能与颗粒内容物的释放、细胞形状变化以及促进血栓形成和止血维持的受体上调有关。
目的
多年来，人们一直在研究热休克蛋白（Hsps）在调节血小板功能中的作用，但尚未彻底研究个别 Hsp 的作用。
方法
我们利用一组特定的 Hsp40、Hsp70、Hsp90 和 Grp94（Hsp90 的内质网同源物）抑制剂来评估它们对血小板功能几个方面的影响。
结果
抑制上述每种 Hsp 均减少 alpha 颗粒释放。相比之下，对致密颗粒释放的影响存在一定的选择性。暴露于 Hsp40、Hsp90 和 Grp94 的抑制剂后，血栓素合成受损，但暴露于 Hsp70 的抑制剂后则不然。我们的抑制剂均降低了活性糖蛋白 IIb/IIIa（GPIIb/IIIa）的表达和纤维蛋白原诱导的血小板形状变化。相比之下，抑制 Hsp40 或 Hsp90 选择性地阻断了聚集。最后，抑制 Hsp70 和 Grp94 均可减少活化血小板与癌细胞的相互作用。
结论
这些数据表明 Hsp 网络在调节血小板活性中的重要性。
Zotero 插件