mTOR regulates GPVI-mediated platelet activation.
mTOR regulates GPVI-mediated platelet activation.
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mTOR 调节 GPVI 介导的血小板活化
DOI：
10.1186/s12967-021-02756-y
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发表时间：
2021-05-10
影响因子：
7.4
通讯作者：
Gao C
中科院分区：
文献类型：
--
作者：
Wang L;Liu G;Wu N;Dai B;Han S;Liu Q;Huang F;Chen Z;Xu W;Xia D;Gao C
由于mTOR（哺乳动物/雷帕霉素机制靶点）基因丢失小鼠在胚胎发育期间死亡，mTOR在血小板中的作用尚未使用基因敲除技术进行评估。方法建立巨核细胞/血小板特异性缺失mTOR小鼠模型，评价mTOR在血小板活化和血栓形成中的作用。结果在低浓度胶原包被表面生长的smtor−/−血小板缺乏血栓形成；然而，当mTOR−/−血小板灌注到高浓度胶原包被表面时，没有观察到血栓形成的缺陷。在fecl3诱导的小鼠肠系膜小动脉血栓形成模型中，野生型（WT）和mTOR - / -小鼠对低程度损伤的反应与闭塞小鼠的比例有显著差异，尤其是在前40分钟内。此外，mTOR−/−血小板在低剂量的糖蛋白VI （GPVI）激动剂胶原相关肽（CRP）和蛋白酶激活受体4 （PAR4）激动剂GYPGKF-NH2的作用下，显示出聚集减少和致密颗粒分泌（ATP释放）；这些缺陷可以通过高浓度激动剂的刺激来克服，这表明反应是剂量依赖性的。在低剂量GPVI或PAR激动剂下，α iib β3在mTOR−/−血小板中的活化降低。此外，用低剂量CRP刺激mTOR−/−血小板可减弱S6K1、S6和Akt Ser473的磷酸化，增加PKCδ Thr505和PKCε Ser729的磷酸化。利用PKCs的同型特异性抑制剂（δ、β和α/β），我们确定PKCδ/ β，尤其是PKCδ，而不是PKCα/β或PKCθ，可能参与低剂量gpvi介导的/ mtor依赖性信号传导。结论mTOR在gpvi依赖性血小板活化和血栓形成中起重要作用。
BackgroundDue to mTOR (mammalian/mechanistic target of rapamycin) gene-loss mice die during embryonic development, the role of mTOR in platelets has not been evaluated using gene knockout technology.MethodsA mouse model with megakaryocyte/platelet-specific deletion of mTOR was established, and be used to evaluate the role of mTOR in platelet activation and thrombus formation.ResultsmTOR−/−platelets were deficient in thrombus formation when grown on low-concentration collagen-coated surfaces; however, no deficiency in thrombus formation was observed when mTOR−/−platelets were perfused on higher concentration collagen-coated surfaces. In FeCl3-induced mouse mesenteric arteriole thrombosis models, wild-type (WT) and mTOR−/−mice displayed significantly different responses to low-extent injury with respect to the ratio of occluded mice, especially within the first 40 min. Additionally, mTOR−/−platelets displayed reduced aggregation and dense granule secretion (ATP release) in response to low doses of the glycoprotein VI (GPVI) agonist collagen related peptide (CRP) and the protease-activated receptor-4 (PAR4) agonist GYPGKF-NH2; these deficiencies were overcame by stimulation with higher concentration agonists, suggesting dose dependence of the response. At low doses of GPVI or PAR agonist, the activation of αIIbβ3in mTOR−/−platelets was reduced. Moreover, stimulation of mTOR−/−platelets with low-dose CRP attenuated the phosphorylation of S6K1, S6 and Akt Ser473, and increased the phosphorylation of PKCδ Thr505 and PKCε Ser729. Using isoform-specific inhibitors of PKCs (δ, ɛ, and α/β), we established that PKCδ/ɛ, and especially PKCδ but not PKCα/β or PKCθ, may be involved in low-dose GPVI-mediated/mTOR-dependent signaling.ConclusionThese observations indicate that mTOR plays an important role in GPVI-dependent platelet activation and thrombus formation.
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DOI：
10.1161/atvbaha.111.242388
发表时间：
2012-05
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Bynagari-Settipalli YS;Lakhani P;Jin J;Bhavaraju K;Rico MC;Kim S;Woulfe D;Kunapuli SP
通讯作者：
Kunapuli SP
DOI：
10.1073/pnas.191369098
发表时间：
2001-09-25
影响因子：
11.1
作者：
Chen, L;Hahn, H;Mochly-Rosen, D
通讯作者：
Mochly-Rosen, D
影响因子：
120.1
作者：
Dobbelstein, Matthias;Moll, Ute
通讯作者：
Moll, Ute
影响因子：
4.8
作者：
Dennis, PB;Pullen, N;Thomas, G
通讯作者：
Thomas, G
DOI：
10.1083/jcb.200703185
发表时间：
2007-11-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Flevaris P;Stojanovic A;Gong H;Chishti A;Welch E;Du X
通讯作者：
Du X