mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation.
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.
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences.
Jun
J
Yang
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Department of Hematology, Zhujiang Hospital.
Xuan
X
Zhou
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences.
Xiaorong
X
Fan
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences.
Min
M
Xiao
Department of Hepatobiliary Surgery, Nanfang Hospital.
Dinghua
D
Yang
Department of Hepatobiliary Surgery, Nanfang Hospital.
Bo
B
Liang
Department of Health Management Center, Nanfang Hospital.
Meng
M
Dai
Department of Health Management Center, Nanfang Hospital.
Lanlan
L
Shan
Department of Vascular Surgery, Nanfang Hospital, and.
Jingbo
J
Lu
Department of Vascular Surgery, Nanfang Hospital, and.
Zhiqi
Z
Lin
Health Management Center, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China;
Rong
R
Liu
Department of Urology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China;
Jun
J
Liu
Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Liping
L
Wang
Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Mei
M
Zhong
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Yu
Y
Jiang
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences.
Xiaochun
0000-0001-9631-4781
X
Bai
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004198:Disease Susceptibility; D005260:Female; D017353:Gene Deletion; D006861:Hydrogen Peroxide / Q000378:metabolism; D063847:Mean Platelet Volume; D000076222:Mechanistic Target of Rapamycin Complex 1; D008533:Megakaryocytes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D015539:Platelet Activation; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D020246:Venous Thrombosis / Q000188:drug therapy / Q000378:metabolism*
D046912:Multiprotein Complexes; D006861:Hydrogen Peroxide; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus