Hyperglycemia exacerbates ischemic stroke outcome independent of platelet glucose uptake.
hyperglycemia
neutrophils
platelets
stroke
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:
02 2021
02 2021
Historique:
received:
11
07
2020
revised:
05
10
2020
accepted:
23
10
2020
pubmed:
30
10
2020
medline:
15
5
2021
entrez:
29
10
2020
Statut:
ppublish
Résumé
Hyperglycemia is a common comorbidity for ischemic stroke and is associated with worsened neurological outcomes. Platelets are central mediators of ischemic stroke and hyperglycemia mediates platelet hyperactivity. In this study, we investigated the contribution of platelet glucose metabolism to ischemic stroke. Mice lacking both Glut1 and Glut3 specifically in platelets (DKO) and their littermate controls (WT) were subjected to 1-hour transient middle cerebral artery occlusion under normoglycemic and streptozotocin-induced hyperglycemic conditions after which stroke outcomes, platelet activation, and platelet-neutrophil aggregate (PNA) formation were examined. Under normoglycemic conditions, DKO mice were protected from ischemic stroke with smaller brain infarct volumes and improved cerebral blood flow. In addition, DKO mice had reduced platelet activation, PNA, and cerebral neutrophil recruitment after stroke. Hyperglycemia significantly increased infarct size and cerebral Evans blue extravasation and worsened neurological outcomes and cerebral blood flow in both WT and DKO mice, abolishing the protective effect witnessed under normoglycemic conditions. Flow cytometric analysis after stroke demonstrated increased platelet activation and neutrophil trafficking to the brain, independent of platelet glucose metabolism. Finally, platelets from healthy DKO mice were unable to become procoagulant upon dual agonist stimulation. Conversely, hyperglycemia increased platelet mitochondrial reactive oxygen species production which potentiated procoagulant platelet formation in WT mice and restored procoagulant platelet formation in DKO mice. Hyperglycemia aggravates ischemic stroke outcome independent of platelet glucose uptake. Furthermore, we demonstrated that hyperglycemia primes procoagulant platelet formation. This underlines the therapeutic potential for strategies targeting procoagulant platelet formation for the treatment of acute ischemic stroke.
Identifiants
pubmed: 33118271
doi: 10.1111/jth.15154
pmc: PMC7902465
mid: NIHMS1669633
pii: S1538-7836(22)00645-6
doi:
Substances chimiques
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
536-546Subventions
Organisme : NIA NIH HHS
ID : K01 AG059892
Pays : United States
Organisme : NINDS NIH HHS
ID : U10 NS086606
Pays : United States
Organisme : NINDS NIH HHS
ID : U24 NS107228
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002538
Pays : United States
Informations de copyright
© 2020 International Society on Thrombosis and Haemostasis.
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