Different Drugs Effect on Mesenchymal Stem Cells Isolated From Abdominal Aortic Aneurysm.
Aorta, Abdominal
/ drug effects
Aortic Aneurysm, Abdominal
/ drug therapy
Cell Separation
Cell Survival
/ drug effects
Cells, Cultured
Doxycycline
/ pharmacology
Female
Humans
Male
Matrix Metalloproteinase 9
/ genetics
Mesenchymal Stem Cells
/ drug effects
Middle Aged
PPAR gamma
/ genetics
Pioglitazone
/ pharmacology
Signal Transduction
Simvastatin
/ pharmacology
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:
01
02
2020
revised:
04
03
2020
accepted:
06
03
2020
pubmed:
17
3
2020
medline:
3
11
2020
entrez:
17
3
2020
Statut:
ppublish
Résumé
Abdominal aortic aneurysm (AAA) is a progressive dilation of the aortic wall, determined by the unbalanced activity of matrix metalloproteinase (MMPs). In vitro and in vivo studies support the pivotal role of MMP-9 to AAA pathogenesis. In our experience, we elucidated the expression of MMP-9 in an ex vivo model of human mesenchymal stem cells isolated from AAA specimen (AAA-MSCs). Thus, MMP-9 inhibition could be an attractive therapeutic strategy for inhibiting AAA degeneration and rupture. Our study was aimed at testing the effect of 3 different drugs (pioglitazone, doxycycline, simvastatin) on MMP-9 and peroxisome proliferator-activated receptor (PPAR)-γ expression in AAA-MSCs. Aneurysmal aortic wall segments were taken from AAA patients after the open surgical treatment. MSCs were isolated from AAA (n = 20) tissues through enzymatic digestion. AAA-MSCs were exposed to different doses of pioglitazone (5-10-25 μM), doxycycline (10-25 μM), and simvastatin (10 μM) for 24 h. The effect of each drug was evaluated in terms of cell survival, by crystal violet stain. MMP-9 and PPAR-γ mRNA were analyzed using real-time PCR. AAA-MSCs were not affected by the exposure to the selected drugs, as shown by the analysis of cell viability. Interestingly, MMP-9 mRNA resulted significantly decreased after each treatment, recording a downregulation of 50% in presence of pioglitazone, 90% with doxycycline, and 40% with exposed to simvastatin, in comparison to untreated cells. We further analyzed the expression of PPAR-γ, target of pioglitazone, observing an upregulation in exposed AAA-MSCs to controls. Our data support the potential therapeutic effect of pioglitazone, doxycycline, and simvastatin on AAA by reducing the MMP-9 expression in a patient-specific model (AAA-MSCs). In addition, pioglitazone drives the increase of PPAR-G, another promising target for AAA therapy. Further studies are necessary to elucidate the mechanism driving this inhibitory pathway, which can reduces the mortality risk associated with AAA rupture.
Sections du résumé
BACKGROUND
BACKGROUND
Abdominal aortic aneurysm (AAA) is a progressive dilation of the aortic wall, determined by the unbalanced activity of matrix metalloproteinase (MMPs). In vitro and in vivo studies support the pivotal role of MMP-9 to AAA pathogenesis. In our experience, we elucidated the expression of MMP-9 in an ex vivo model of human mesenchymal stem cells isolated from AAA specimen (AAA-MSCs). Thus, MMP-9 inhibition could be an attractive therapeutic strategy for inhibiting AAA degeneration and rupture. Our study was aimed at testing the effect of 3 different drugs (pioglitazone, doxycycline, simvastatin) on MMP-9 and peroxisome proliferator-activated receptor (PPAR)-γ expression in AAA-MSCs.
METHODS
METHODS
Aneurysmal aortic wall segments were taken from AAA patients after the open surgical treatment. MSCs were isolated from AAA (n = 20) tissues through enzymatic digestion. AAA-MSCs were exposed to different doses of pioglitazone (5-10-25 μM), doxycycline (10-25 μM), and simvastatin (10 μM) for 24 h. The effect of each drug was evaluated in terms of cell survival, by crystal violet stain. MMP-9 and PPAR-γ mRNA were analyzed using real-time PCR.
RESULTS
RESULTS
AAA-MSCs were not affected by the exposure to the selected drugs, as shown by the analysis of cell viability. Interestingly, MMP-9 mRNA resulted significantly decreased after each treatment, recording a downregulation of 50% in presence of pioglitazone, 90% with doxycycline, and 40% with exposed to simvastatin, in comparison to untreated cells. We further analyzed the expression of PPAR-γ, target of pioglitazone, observing an upregulation in exposed AAA-MSCs to controls.
CONCLUSIONS
CONCLUSIONS
Our data support the potential therapeutic effect of pioglitazone, doxycycline, and simvastatin on AAA by reducing the MMP-9 expression in a patient-specific model (AAA-MSCs). In addition, pioglitazone drives the increase of PPAR-G, another promising target for AAA therapy. Further studies are necessary to elucidate the mechanism driving this inhibitory pathway, which can reduces the mortality risk associated with AAA rupture.
Identifiants
pubmed: 32173476
pii: S0890-5096(20)30194-1
doi: 10.1016/j.avsg.2020.03.001
pii:
doi:
Substances chimiques
PPAR gamma
0
PPARG protein, human
0
Simvastatin
AGG2FN16EV
MMP9 protein, human
EC 3.4.24.35
Matrix Metalloproteinase 9
EC 3.4.24.35
Doxycycline
N12000U13O
Pioglitazone
X4OV71U42S
Types de publication
Comparative Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
490-496Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.