Factor Xa Inhibition by Rivaroxaban Modified Mitochondrial-Associated Proteins in Human Abdominal Aortic Aneurysms.

Abstract

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:

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:

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:

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.

• Authors: José J Zamorano-Leon, Mariano de la Serna-Soto, Guillermo Moñux, Gala Freixer, Khaoula Zekri-Nechar, Maday Cabrero-Fernandez, Antonio Segura, Antonio Gonzalez-Cantalapiedra, Javier Serrano, Antonio López Farré
• Journal: Annals of vascular surgery (Ann Vasc Surg) Vol. 67 Pg. 482-489 (Aug 2020) ISSN: 1615-5947 [Electronic] Netherlands
• PMID: 32173474 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Factor Xa Inhibitors
• Mitochondrial Proteins
• Rivaroxaban

Topics

• Adult
• Aged
• Aorta, Abdominal (drug effects, metabolism, pathology)
• Aortic Aneurysm, Abdominal (drug therapy, metabolism, pathology)
• Case-Control Studies
• Factor Xa Inhibitors (pharmacology)
• Female
• Humans
• Male
• Middle Aged
• Mitochondria (drug effects, metabolism, pathology)
• Mitochondrial Proteins (metabolism)
• Mitophagy (drug effects)
• Rivaroxaban (pharmacology)
• Thrombosis (drug therapy, metabolism, pathology)