| First Author | Wang L | Year | 2021 |
| Journal | J Transl Med | Volume | 19 |
| Issue | 1 | Pages | 201 |
| PubMed ID | 33971888 | Mgi Jnum | J:370073 |
| Mgi Id | MGI:7486376 | Doi | 10.1186/s12967-021-02756-y |
| Citation | Wang L, et al. (2021) mTOR regulates GPVI-mediated platelet activation. J Transl Med 19(1):201 |
| abstractText | BACKGROUND: Due 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. METHODS: A 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. RESULTS: mTOR(-/-) 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 FeCl(3)-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-NH(2); 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 alpha(IIb)beta(3) in 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 PKCdelta Thr505 and PKCepsilon Ser729. Using isoform-specific inhibitors of PKCs (delta, varepsilon, and alpha/beta), we established that PKCdelta/varepsilon, and especially PKCdelta but not PKCalpha/beta or PKCtheta, may be involved in low-dose GPVI-mediated/mTOR-dependent signaling. CONCLUSION: These observations indicate that mTOR plays an important role in GPVI-dependent platelet activation and thrombus formation. |
