mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation.

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.

• Authors: Jun Yang, Xuan Zhou, Xiaorong Fan, Min Xiao, Dinghua Yang, Bo Liang, Meng Dai, Lanlan Shan, Jingbo Lu, Zhiqi Lin, Rong Liu, Jun Liu, Liping Wang, Mei Zhong, Yu Jiang, Xiaochun Bai
• Journal: Blood (Blood) Vol. 128 Issue 5 Pg. 615-24 (08 04 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 27288518 (Publication Type: Journal Article)
• Copyright: © 2016 by The American Society of Hematology.

Chemical References

• Multiprotein Complexes
• Hydrogen Peroxide
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Aging (metabolism)
• Animals
• Blood Platelets (metabolism)
• Cell Differentiation (drug effects)
• Cell Size (drug effects)
• Disease Susceptibility
• Female
• Gene Deletion
• Hydrogen Peroxide (metabolism)
• Mean Platelet Volume
• Mechanistic Target of Rapamycin Complex 1
• Megakaryocytes (metabolism)
• Mice, Inbred C57BL
• Multiprotein Complexes (metabolism)
• Platelet Activation
• Sirolimus (pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases (metabolism)
• Venous Thrombosis (drug therapy, metabolism)