Induction of HO-1 by 5, 8-Dihydroxy-4′,7-Dimethoxyflavone via Activation of ROSp38 MAPKNrf2 Attenuates Thrombin-Induced Connective Tissue Growth Factor Expression in Human Cardiac Fibroblasts
Joint Authors
Hsiao, Li-Der
Leu, Yann-Lii
Yang, Chien-Chung
Tseng, Hui-Ching
Situmorang, Jiro Hasegawa
Yang, Chuen-Mao
Lin, Hsin-Hui
Source
Oxidative Medicine and Cellular Longevity
Issue
Vol. 2020, Issue 2020 (31 Dec. 2020), pp.1-18, 18 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2020-12-04
Country of Publication
Egypt
No. of Pages
18
Main Subjects
Abstract EN
Heme oxygenase-1 (HO-1) has been shown to exert as an antioxidant and anti-inflammatory enzyme in cardiovascular inflammatory diseases.
Flavonoids have been demonstrated to display anti-inflammatory and antioxidant effects through the induction of HO-1.
5,8-Dihydroxy-4′,7-dimethoxyflavone (DDF), one of the flavonoid compounds, is isolated from Reevesia formosana.
Whether DDF induced HO-1 expression on human cardiac fibroblasts (HCFs) remained unknown.
Here, we found that DDF time- and concentration-dependently induced HO-1 protein and mRNA expression, which was attenuated by pretreatment with reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) in HCFs.
DDF-enhanced ROS generation was attenuated by NAC, but not by either diphenyleneiodonium chloride (DPI, Nox inhibitor) or MitoTempol (mitochondrial ROS scavenger).
Interestingly, pretreatment with glutathione (GSH) inhibited DDF-induced HO-1 expression.
The ratio of GSH/GSSG was time-dependently decreased in DDF-treated HCFs.
DDF-induced HO-1 expression was attenuated by an inhibitor of p38 MAPK (p38i VIII) or siRNA, but not by MEK1/2 (PD98059) or JNK1/2 (SP600125).
DDF-stimulated p38 MAPK phosphorylation was inhibited by GSH or p38i VIII.
Moreover, DDF-induced HO-1 expression was mediated through Nrf2 phosphorylation and translocation into the nucleus which was attenuated by NAC or p38 siRNA.
DDF also stimulated antioxidant response element (ARE) promoter activity which was inhibited by NAC, GSH, or p38i VIII.
Interaction between Nrf2 and the ARE-binding sites on the HO-1 promoter was revealed by chromatin immunoprecipitation assay, which was attenuated by NAC, GSH, or p38i VIII.
We further evaluated the functional effect of HO-1 expression on the thrombin-induced fibrotic responses.
Our result indicated that the induction of HO-1 by DDF can attenuate the thrombin-induced connective tissue growth factor expression.
These results suggested that DDF-induced HO-1 expression is, at least, mediated through the activation of the ROS-dependent p38 MAPK/Nrf2 signaling pathway in HCFs.
Thus, the upregulation of HO-1 by DDF could be a candidate for the treatment of heart fibrosis.
American Psychological Association (APA)
Yang, Chien-Chung& Hsiao, Li-Der& Lin, Hsin-Hui& Tseng, Hui-Ching& Situmorang, Jiro Hasegawa& Leu, Yann-Lii…[et al.]. 2020. Induction of HO-1 by 5, 8-Dihydroxy-4′,7-Dimethoxyflavone via Activation of ROSp38 MAPKNrf2 Attenuates Thrombin-Induced Connective Tissue Growth Factor Expression in Human Cardiac Fibroblasts. Oxidative Medicine and Cellular Longevity،Vol. 2020, no. 2020, pp.1-18.
https://search.emarefa.net/detail/BIM-1203629
Modern Language Association (MLA)
Yang, Chien-Chung…[et al.]. Induction of HO-1 by 5, 8-Dihydroxy-4′,7-Dimethoxyflavone via Activation of ROSp38 MAPKNrf2 Attenuates Thrombin-Induced Connective Tissue Growth Factor Expression in Human Cardiac Fibroblasts. Oxidative Medicine and Cellular Longevity No. 2020 (2020), pp.1-18.
https://search.emarefa.net/detail/BIM-1203629
American Medical Association (AMA)
Yang, Chien-Chung& Hsiao, Li-Der& Lin, Hsin-Hui& Tseng, Hui-Ching& Situmorang, Jiro Hasegawa& Leu, Yann-Lii…[et al.]. Induction of HO-1 by 5, 8-Dihydroxy-4′,7-Dimethoxyflavone via Activation of ROSp38 MAPKNrf2 Attenuates Thrombin-Induced Connective Tissue Growth Factor Expression in Human Cardiac Fibroblasts. Oxidative Medicine and Cellular Longevity. 2020. Vol. 2020, no. 2020, pp.1-18.
https://search.emarefa.net/detail/BIM-1203629
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1203629