Factor Xa Inhibition by Rivaroxaban Modified Mitochondrial-Associated Proteins in Human Abdominal Aortic Aneurysms.
Adult
Aged
Aorta, Abdominal
/ drug effects
Aortic Aneurysm, Abdominal
/ drug therapy
Case-Control Studies
Factor Xa Inhibitors
/ pharmacology
Female
Humans
Male
Middle Aged
Mitochondria
/ drug effects
Mitochondrial Proteins
/ metabolism
Mitophagy
/ drug effects
Rivaroxaban
/ pharmacology
Thrombosis
/ drug therapy
Journal
Annals of vascular surgery
ISSN: 1615-5947
Titre abrégé: Ann Vasc Surg
Pays: Netherlands
ID NLM: 8703941
Informations de publication
Date de publication:
Aug 2020
Aug 2020
Historique:
received:
10
01
2020
accepted:
20
02
2020
pubmed:
17
3
2020
medline:
3
11
2020
entrez:
17
3
2020
Statut:
ppublish
Résumé
The presence of intraluminal thrombus and mitochondrial dysfunction in human abdominal aortic aneurysms (AAAs) have been associated with aneurysmal growth and rupture. The objective of the study was to study if endogenous factor Xa (FXa) may modulate mitochondrial functionality and expression of proteins associated with mitophagy in human AAAs. AAA sites with intraluminal thrombus were obtained from 6 patients undergoing elective AAA surgery repair. Control samples were collected from 6 organ donors. The effect of FXa was analyzed by in vitro incubation of AAA with 50 nmol/L rivaroxaban, an oral FXa inhibitor. The enzymatic activities of citrate synthase, a biomarker of mitochondrial density, and cytochrome C oxidase, a biomarker of mitochondrial respiratory chain functionality, were significantly reduced in the AAA sites with respect to the healthy aorta (citrate synthase activity in μU/min/μg protein: control: 3.51 ± 0.22 vs. AAA: 0.37 ± 0.15.; P < 0.01; cytochrome C oxidase activity in μOD/min/μg protein: control: 8.05 ± 1.57 vs. AAA: 3.29 ± 1.05; P < 0.05). The addition of rivaroxaban to AAA reverted the activity of both citrate synthase and cytochrome C oxidase to similar values to control. Mitochondrial Drp-1 expression was higher in AAA sites than in either control aortas or rivaroxaban-incubated AAA sites. Cytosolic content of Drp-1 phosphorylated at Ser637, mitochondrial Parkin, and mitochondrial PINK1-Parkin interaction were significantly reduced in the AAA sites with respect to control aortas. For all these parameters, rivaroxaban-incubated AAA showed similar values compared with control aortas. In human AAA, rivaroxaban improved mitochondrial functionality that was associated with changes in proteins related to mitophagy. Its opens possible new effects of endogenous FXa on the mitochondria in the human AAA site.
Sections du résumé
BACKGROUND
BACKGROUND
The presence of intraluminal thrombus and mitochondrial dysfunction in human abdominal aortic aneurysms (AAAs) have been associated with aneurysmal growth and rupture. The objective of the study was to study if endogenous factor Xa (FXa) may modulate mitochondrial functionality and expression of proteins associated with mitophagy in human AAAs.
METHODS
METHODS
AAA sites with intraluminal thrombus were obtained from 6 patients undergoing elective AAA surgery repair. Control samples were collected from 6 organ donors. The effect of FXa was analyzed by in vitro incubation of AAA with 50 nmol/L rivaroxaban, an oral FXa inhibitor.
RESULTS
RESULTS
The enzymatic activities of citrate synthase, a biomarker of mitochondrial density, and cytochrome C oxidase, a biomarker of mitochondrial respiratory chain functionality, were significantly reduced in the AAA sites with respect to the healthy aorta (citrate synthase activity in μU/min/μg protein: control: 3.51 ± 0.22 vs. AAA: 0.37 ± 0.15.; P < 0.01; cytochrome C oxidase activity in μOD/min/μg protein: control: 8.05 ± 1.57 vs. AAA: 3.29 ± 1.05; P < 0.05). The addition of rivaroxaban to AAA reverted the activity of both citrate synthase and cytochrome C oxidase to similar values to control. Mitochondrial Drp-1 expression was higher in AAA sites than in either control aortas or rivaroxaban-incubated AAA sites. Cytosolic content of Drp-1 phosphorylated at Ser637, mitochondrial Parkin, and mitochondrial PINK1-Parkin interaction were significantly reduced in the AAA sites with respect to control aortas. For all these parameters, rivaroxaban-incubated AAA showed similar values compared with control aortas.
CONCLUSIONS
CONCLUSIONS
In human AAA, rivaroxaban improved mitochondrial functionality that was associated with changes in proteins related to mitophagy. Its opens possible new effects of endogenous FXa on the mitochondria in the human AAA site.
Identifiants
pubmed: 32173474
pii: S0890-5096(20)30193-X
doi: 10.1016/j.avsg.2020.02.005
pii:
doi:
Substances chimiques
Factor Xa Inhibitors
0
Mitochondrial Proteins
0
Rivaroxaban
9NDF7JZ4M3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
482-489Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.