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mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation.
- Source :
-
Blood [Blood] 2016 Aug 04; Vol. 128 (5), pp. 615-24. Date of Electronic Publication: 2016 Jun 10. - Publication Year :
- 2016
-
Abstract
- Aging is associated with an increased incidence of venous thromboembolism (VTE), resulting in significant morbidity and mortality in the elderly. Platelet hyperactivation is linked to aging-related VTE. However, the mechanisms through which aging enhances platelet activation and susceptibility to VTE are poorly understood. In this study, we demonstrated that mechanistic target of rapamycin complex 1 (mTORC1) signaling is essential for aging-related platelet hyperactivation and VTE. mTORC1 was hyperactivated in platelets and megakaryocytes (MKs) from aged mice, accompanied by elevated mean platelet volume (MPV) and platelet activation. Inhibition of mTORC1 with rapamycin led to a significant reduction in susceptibility to experimental deep vein thrombosis (DVT) in aged mice (P < .01). To ascertain the specific role of platelet mTORC1 activation in DVT, we generated mice with conditional ablation of the mTORC1-specific component gene Raptor in MKs and platelets (Raptor knockout). These mice developed markedly smaller and lighter thrombi, compared with wild-type littermates (P < .01) in experimental DVT. Mechanistically, increased reactive oxygen species (ROS) production with aging induced activation of mTORC1 in MKs and platelets, which, in turn, enhanced bone marrow MK size, MPV, and platelet activation to promote aging-related VTE. ROS scavenger administration induced a significant decrease (P < .05) in MK size, MPV, and platelet activation in aged mice. Our findings collectively demonstrate that mTORC1 contributes to enhanced venous thrombotic susceptibility in aged mice via elevation of platelet size and activation.<br /> (© 2016 by The American Society of Hematology.)
- Subjects :
- Animals
Cell Differentiation drug effects
Cell Size drug effects
Disease Susceptibility
Female
Gene Deletion
Hydrogen Peroxide metabolism
Mechanistic Target of Rapamycin Complex 1
Megakaryocytes metabolism
Mice, Inbred C57BL
Sirolimus pharmacology
Sirolimus therapeutic use
Venous Thrombosis drug therapy
Aging metabolism
Blood Platelets metabolism
Mean Platelet Volume
Multiprotein Complexes metabolism
Platelet Activation
TOR Serine-Threonine Kinases metabolism
Venous Thrombosis metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 128
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 27288518
- Full Text :
- https://doi.org/10.1182/blood-2015-10-672964