Tranexamic acid suppresses the release of mitochondrial DNA, protects the endothelial monolayer and enhances oxidative phosphorylation.
Animals
DNA Damage
/ drug effects
DNA, Mitochondrial
/ drug effects
Endothelial Cells
/ drug effects
Granulocytes
/ drug effects
Hemorrhage
/ drug therapy
Humans
Mice
Mitochondria
/ drug effects
Mitophagy
/ drug effects
Oxidative Phosphorylation
/ drug effects
Tranexamic Acid
/ pharmacology
Wounds and Injuries
/ drug therapy
endothelial cell
mitochondria
mitochondrial DNA
mitophagy
tranexamic acid
Journal
Journal of cellular physiology
ISSN: 1097-4652
Titre abrégé: J Cell Physiol
Pays: United States
ID NLM: 0050222
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
08
11
2018
revised:
10
03
2019
accepted:
19
03
2019
pubmed:
4
4
2019
medline:
30
5
2020
entrez:
4
4
2019
Statut:
ppublish
Résumé
Damage-associated molecular patterns, including mitochondrial DNA (mtDNA) are released during hemorrhage resulting in the development of endotheliopathy. Tranexamic acid (TXA), an antifibrinolytic drug used in hemorrhaging patients, enhances their survival despite the lack of a comprehensive understanding of its cellular mechanisms of action. The present study is aimed to elucidate these mechanisms, with a focus on mitochondria. We found that TXA inhibits the release of endogenous mtDNA from granulocytes and endothelial cells. Furthermore, TXA attenuates the loss of the endothelial monolayer integrity induced by exogenous mtDNA. Using the Seahorse XF technology, it was demonstrated that TXA strongly stimulates mitochondrial respiration. Studies using Mitotracker dye, cells derived from mito-QC mice, and the ActivSignal IPAD assay, indicate that TXA stimulates biogenesis of mitochondria and inhibits mitophagy. These findings open the potential for improvement of the strategies of TXA applications in trauma patients and the development of more efficient TXA derivatives.
Identifiants
pubmed: 30941770
doi: 10.1002/jcp.28603
pmc: PMC6660401
mid: NIHMS1020115
doi:
Substances chimiques
DNA, Mitochondrial
0
Tranexamic Acid
6T84R30KC1
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
19121-19129Subventions
Organisme : NIGMS NIH HHS
ID : P30 GM106391
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM115516
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121301
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103391
Pays : United States
Informations de copyright
© 2019 Wiley Periodicals, Inc.
Références
J Trauma. 2003 May;54(5 Suppl):S169-76
pubmed: 12768121
Hematol Oncol Clin North Am. 2007 Feb;21(1):89-101
pubmed: 17258120
Annu Rev Pathol. 2008;3:99-126
pubmed: 18039143
Angiogenesis. 2008;11(2):109-19
pubmed: 18293091
Anesthesiology. 2008 Oct;109(4):723-40
pubmed: 18813052
Neoplasia. 2009 Jul;11(7):615-28
pubmed: 19568407
Nature. 2010 Mar 4;464(7285):104-7
pubmed: 20203610
Lancet. 2010 Jul 3;376(9734):23-32
pubmed: 20554319
Autophagy. 2010 Nov;6(8):1090-106
pubmed: 20890124
J Vis Exp. 2010 Dec 14;(46):null
pubmed: 21178973
Arch Surg. 2012 Feb;147(2):113-9
pubmed: 22006852
PLoS One. 2013;8(3):e59989
pubmed: 23527291
Methods Mol Biol. 2015;1241:23-38
pubmed: 25308485
Biochim Biophys Acta. 2015 Oct;1853(10 Pt B):2775-83
pubmed: 25753537
Anaesthesiol Intensive Ther. 2015;47(4):339-50
pubmed: 25797505
Vascul Pharmacol. 2015 Aug;71:31-6
pubmed: 25869514
Orthop Clin North Am. 2016 Jan;47(1):137-43
pubmed: 26614928
Acta Obstet Gynecol Scand. 2016 Jan;95(1):28-37
pubmed: 26698831
Clin Ther. 2016 May;38(5):1017-28
pubmed: 27021609
J Trauma Acute Care Surg. 2016 Aug;81(2):358-65
pubmed: 27027557
Transfusion. 2016 Apr;56 Suppl 2:S203-7
pubmed: 27100757
Clin Ther. 2016 May;38(5):1042-53
pubmed: 27101817
Blood. 2016 Aug 18;128(7):993-1002
pubmed: 27402974
J Cell Biol. 2016 Aug 1;214(3):333-45
pubmed: 27458135
Clin Rev Allergy Immunol. 2018 Jun;54(3):412-431
pubmed: 27672078
J Trauma Acute Care Surg. 2017 Jun;82(6):1080-1086
pubmed: 28328682
Proc Natl Acad Sci U S A. 1979 Jun;76(6):2779-83
pubmed: 288066
J Biol Chem. 2017 Oct 13;292(41):16983-16998
pubmed: 28821609
J Trauma Acute Care Surg. 2018 Jan;84(1):75-80
pubmed: 29040203
Acta Physiol (Oxf). 2018 Aug;223(4):e13074
pubmed: 29660243
Traffic. 2018 Aug;19(8):569-577
pubmed: 29663589
J Trauma Acute Care Surg. 2019 Apr;86(4):617-624
pubmed: 30589751
Br J Cancer Suppl. 1988 Dec;9:41-5
pubmed: 3076064
J Leukoc Biol. 1995 Dec;58(6):659-66
pubmed: 7499963
Biochemistry. 1993 Oct 19;32(41):10936-43
pubmed: 8218159