A high-fat diet delays plasmin generation in a thrombomodulin-dependent manner in mice.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
07 05 2020
07 05 2020
Historique:
received:
21
11
2019
accepted:
02
02
2020
pubmed:
22
4
2020
medline:
1
1
2021
entrez:
22
4
2020
Statut:
ppublish
Résumé
Obesity is a prevalent prothrombotic risk factor marked by enhanced fibrin formation and suppressed fibrinolysis. Fibrin both promotes thrombotic events and drives obesity pathophysiology, but a lack of essential analytical tools has left fibrinolytic mechanisms affected by obesity poorly defined. Using a plasmin-specific fluorogenic substrate, we developed a plasmin generation (PG) assay for mouse plasma that is sensitive to tissue plasminogen activator, α2-antiplasmin, active plasminogen activator inhibitor (PAI-1), and fibrin formation, but not fibrin crosslinking. Compared with plasmas from mice fed a control diet, plasmas from mice fed a high-fat diet (HFD) showed delayed PG and reduced PG velocity. Concurrent to impaired PG, HFD also enhanced thrombin generation (TG). The collective impact of abnormal TG and PG in HFD-fed mice produced normal fibrin formation kinetics but delayed fibrinolysis. Functional and proteomic analyses determined that delayed PG in HFD-fed mice was not due to altered levels of plasminogen, α2-antiplasmin, or fibrinogen. Changes in PG were also not explained by elevated PAI-1 because active PAI-1 concentrations required to inhibit the PG assay were 100-fold higher than circulating concentrations in mice. HFD-fed mice had increased circulating thrombomodulin, and inhibiting thrombomodulin or thrombin-activatable fibrinolysis inhibitor (TAFI) normalized PG, revealing a thrombomodulin- and TAFI-dependent antifibrinolytic mechanism. Integrating kinetic parameters to calculate the metric of TG/PG ratio revealed a quantifiable net shift toward a prothrombotic phenotype in HFD-fed mice. Integrating TG and PG measurements may define a prothrombotic risk factor in diet-induced obesity.
Identifiants
pubmed: 32315384
pii: S0006-4971(20)62051-1
doi: 10.1182/blood.2019004267
pmc: PMC7205812
doi:
Substances chimiques
THBD protein, mouse
0
Thrombomodulin
0
Thrombin
EC 3.4.21.5
Fibrinolysin
EC 3.4.21.7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1704-1717Subventions
Organisme : NHLBI NIH HHS
ID : R61 HL141791
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES017537
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL126974
Pays : United States
Organisme : NHLBI NIH HHS
ID : R33 HL141791
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211098
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL143403
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112778
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL055374
Pays : United States
Informations de copyright
© 2020 by The American Society of Hematology.
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