Chalcone flavokawain A attenuates TGF-β1-induced fibrotic pathology via inhibition of ROS/Smad3 signaling pathways and induction of Nrf2/ARE-mediated antioxidant genes in vascular smooth muscle cells.
Actins
/ genetics
Animals
Antioxidant Response Elements
/ drug effects
Antioxidants
/ pharmacology
Aorta
/ cytology
Cell Line
Cell Movement
/ drug effects
Chalcone
/ analogs & derivatives
Fibronectins
/ genetics
Fibrosis
/ prevention & control
Gene Expression Regulation
Heme Oxygenase-1
/ genetics
Matrix Metalloproteinase 2
/ genetics
Matrix Metalloproteinase 9
/ genetics
Models, Biological
Myocytes, Smooth Muscle
/ cytology
NAD(P)H Dehydrogenase (Quinone)
/ genetics
NF-E2-Related Factor 2
/ antagonists & inhibitors
Rats
Reactive Oxygen Species
/ antagonists & inhibitors
Signal Transduction
Smad3 Protein
/ antagonists & inhibitors
Tissue Inhibitor of Metalloproteinase-1
/ genetics
Transforming Growth Factor beta1
/ pharmacology
Nrf2
ROS
Smad3
TGF-β1p
fibrosis
flavokawain A
smooth muscle cells
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
14
03
2018
revised:
28
09
2018
accepted:
28
09
2018
pubmed:
15
12
2018
medline:
19
6
2020
entrez:
15
12
2018
Statut:
ppublish
Résumé
TGF-β1 plays a crucial role in the pathogenesis of vascular fibrotic diseases. Chalcones are reportedly cancer chemo-preventive food components that are rich in fruits and vegetables. In this study, flavokawain A (FKA, 2-30 μM), a naturally occurring chalcone in kava extracts, was evaluated for its anti-fibrotic and antioxidant properties in TGF-β1-stimulated vascular smooth muscle (A7r5) cells, as well as its underlying molecular mechanism of action. Immunofluorescence data showed down-regulated F-actin expression with FKA treatment in TGF-β1-stimulated A7r5 cells. Western blotting demonstrated that FKA treatment suppressed the expression of α-SMA and fibronectin proteins under TGF-β1 stimulation. Findings from wound-healing and invasion experiments showed that FKA inhibits TGF-β1-mediated migration and invasion. Western blotting demonstrated that treatment with FKA down-regulated MMP-9 and MMP-2 and up-regulated TIMP-1 expression. Further evidence showed that FKA decreased TGF-β1-mediated phosphorylation and the transcriptional activity of Smad3. TGF-β1-induced excessive ROS production was remarkably reversed by FKA treatment in A7r5 cells, and inhibition by FKA or N-acetylcysteine (NAC) substantially diminished TGF-β1-induced p-Smad3 activation and wound-healing migration. Interestingly, FKA-mediated antioxidant properties were associated with increased nuclear translocation of Nrf2 and elevated antioxidant response element (ARE) luciferase activity. Activation of Nrf2/ARE signaling was accompanied by the induction of HO-1, NQO-1 and γ-GCLC genes in FKA-treated A7r5 cells. Notably, silencing of Nrf2 (siRNA transfection) significantly diminished the FKA-mediated antioxidant effects, indicating that FKA may inhibit TGF-β1-induced fibrosis through suppressing ROS generation in A7r5 cells. Our results suggested that anti-fibrotic and antioxidant activities of the chalcone flavokawain A may contribute to the development of food-based chemo-preventive drugs for fibrotic diseases.
Identifiants
pubmed: 30549180
doi: 10.1111/jcmm.13973
pmc: PMC6349172
doi:
Substances chimiques
Actins
0
Antioxidants
0
Fibronectins
0
NF-E2-Related Factor 2
0
Nfe2l2 protein, rat
0
Reactive Oxygen Species
0
Smad3 Protein
0
Smad3 protein, rat
0
TIMP1 protein, rat
0
Tgfb1 protein, rat
0
Tissue Inhibitor of Metalloproteinase-1
0
Transforming Growth Factor beta1
0
flavokawain A
0
smooth muscle actin, rat
0
Chalcone
5S5A2Q39HX
Heme Oxygenase-1
EC 1.14.14.18
NAD(P)H Dehydrogenase (Quinone)
EC 1.6.5.2
NQO1 protein, rat
EC 1.6.5.2
Matrix Metalloproteinase 2
EC 3.4.24.24
Mmp2 protein, rat
EC 3.4.24.24
Matrix Metalloproteinase 9
EC 3.4.24.35
Mmp9 protein, rat
EC 3.4.24.35
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
775-788Informations de copyright
© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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