Aging-related Alterations in mTOR Signaling Promote Platelet Hyperreactivity and Thrombosis.
aging
phosphoproteome
platelets
tandem mass tag
thrombosis
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
05 Jun 2024
05 Jun 2024
Historique:
received:
05
01
2024
revised:
12
04
2024
accepted:
13
05
2024
medline:
8
6
2024
pubmed:
8
6
2024
entrez:
7
6
2024
Statut:
aheadofprint
Résumé
Aging is an independent risk factor for the development of cardiovascular, thrombotic and other chronic diseases. However, mechanisms of platelet hyperactivation in aging remain poorly understood. Here, we examine whether and how aging alters intracellular signaling in platelets to support platelet hyperactivity and thrombosis. Quantitative mass spectrometry with tandem mass tag (TMT) labeling systematically measured protein phosphorylation in platelets from healthy aged (>65 years) and young human (<45 years) subjects. The role of platelet mTOR in aging-induced platelet hyperreactivity was assessed using pharmacological mTOR inhibition and a platelet-specific mTOR-deficient mouse model (mTOR Quantitative phosphoproteomics uncovered differential site-specific protein phosphorylation within mTOR, Rho GTPase and MAPK pathways in platelets from aged donors. Western blot confirmed constitutive activation of the mTOR pathway in platelets from both aged humans and mice, which was associated with increased aggregation compared to young controls. Inhibition of mTOR either with Torin 1 in aged humans, or genetic deletion in aged mice, reversed platelet hyperreactivity. In a collagen-epinephrine pulmonary thrombosis model, aged wild-type (mTOR Aging-related changes in mTOR phosphorylation enhance Rac1 and p38 activation, to enhance thromboxane generation, platelet hyperactivity and thrombosis.
Sections du résumé
BACKGROUND AND OBJECTIVES
OBJECTIVE
Aging is an independent risk factor for the development of cardiovascular, thrombotic and other chronic diseases. However, mechanisms of platelet hyperactivation in aging remain poorly understood. Here, we examine whether and how aging alters intracellular signaling in platelets to support platelet hyperactivity and thrombosis.
METHODS
METHODS
Quantitative mass spectrometry with tandem mass tag (TMT) labeling systematically measured protein phosphorylation in platelets from healthy aged (>65 years) and young human (<45 years) subjects. The role of platelet mTOR in aging-induced platelet hyperreactivity was assessed using pharmacological mTOR inhibition and a platelet-specific mTOR-deficient mouse model (mTOR
RESULTS
RESULTS
Quantitative phosphoproteomics uncovered differential site-specific protein phosphorylation within mTOR, Rho GTPase and MAPK pathways in platelets from aged donors. Western blot confirmed constitutive activation of the mTOR pathway in platelets from both aged humans and mice, which was associated with increased aggregation compared to young controls. Inhibition of mTOR either with Torin 1 in aged humans, or genetic deletion in aged mice, reversed platelet hyperreactivity. In a collagen-epinephrine pulmonary thrombosis model, aged wild-type (mTOR
CONCLUSION
CONCLUSIONS
Aging-related changes in mTOR phosphorylation enhance Rac1 and p38 activation, to enhance thromboxane generation, platelet hyperactivity and thrombosis.
Identifiants
pubmed: 38849085
pii: S1538-7836(24)00317-9
doi: 10.1016/j.jtha.2024.05.025
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.