BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells
Activation of hepatic stellate cells (HSCs) is a critical pathogenic feature of liver fibrosis and cirrhosis. BAY 41-2272 is a canonical non-nitric oxide (NO)-based soluble guanylyl cyclase (sGC) stimulator that triggers cyclic guanosine monophosphate (cGMP) signaling for attenuation of fibrotic dis...
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doaj-2dc9feabed724496af7cbd0e4801ced02020-11-25T02:31:00ZengMDPI AGBiomedicines2227-90592020-09-01833033010.3390/biomedicines8090330BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate CellsPo-Jen Chen0Liang-Mou Kuo1Yi-Hsiu Wu2Yu-Chia Chang3Kuei-Hung Lai4Tsong-Long Hwang5Department of Cosmetic Science, Providence University, Taichung 433719, TaiwanDepartment of General Surgery, Chang Gung Memorial Hospital at Chiayi, Chiayi 613016, TaiwanGraduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333323, TaiwanResearch Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333323, TaiwanResearch Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333323, TaiwanGraduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333323, TaiwanActivation of hepatic stellate cells (HSCs) is a critical pathogenic feature of liver fibrosis and cirrhosis. BAY 41-2272 is a canonical non-nitric oxide (NO)-based soluble guanylyl cyclase (sGC) stimulator that triggers cyclic guanosine monophosphate (cGMP) signaling for attenuation of fibrotic disorders; however, the impact of BAY 41-2272 on HSC activation remains ill-defined. Transforming growth factor (TGF)β and its downstream connective tissue growth factor (CTGF or cellular communication network factor 2, CCN2) are critical fibrogenic cytokines for accelerating HSC activation. Here, we identified that BAY 41-2272 significantly inhibited the TGFβ1-induced mRNA and protein expression of CTGF in mouse primary HSCs. Indeed, BAY 41-2272 increased the sGC activity and cGMP levels that were potentiated by two NO donors and inhibited by a specific sGC inhibitor, ODQ. Surprisingly, the inhibitory effects of BAY 41-2272 on CTGF expression were independent of the sGC/cGMP pathway in TGFβ1-activated primary HSCs. BAY 41-2272 selectively restricted the TGFβ1-induced phosphorylation of Akt but not canonical Smad2/3 in primary HSCs. Together, we illustrate a unique framework of BAY 41-2272 for inhibiting TGFβ1-induced CTGF upregulation and HSC activation via a noncanonical Akt-dependent but sGC/cGMP-independent pathway.https://www.mdpi.com/2227-9059/8/9/330AktBAY 41-2272CTGFhepatic stellate cellsGC |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Po-Jen Chen Liang-Mou Kuo Yi-Hsiu Wu Yu-Chia Chang Kuei-Hung Lai Tsong-Long Hwang |
spellingShingle |
Po-Jen Chen Liang-Mou Kuo Yi-Hsiu Wu Yu-Chia Chang Kuei-Hung Lai Tsong-Long Hwang BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells Biomedicines Akt BAY 41-2272 CTGF hepatic stellate cell sGC |
author_facet |
Po-Jen Chen Liang-Mou Kuo Yi-Hsiu Wu Yu-Chia Chang Kuei-Hung Lai Tsong-Long Hwang |
author_sort |
Po-Jen Chen |
title |
BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells |
title_short |
BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells |
title_full |
BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells |
title_fullStr |
BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells |
title_full_unstemmed |
BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells |
title_sort |
bay 41-2272 attenuates ctgf expression via sgc/cgmp-independent pathway in tgfβ1-activated hepatic stellate cells |
publisher |
MDPI AG |
series |
Biomedicines |
issn |
2227-9059 |
publishDate |
2020-09-01 |
description |
Activation of hepatic stellate cells (HSCs) is a critical pathogenic feature of liver fibrosis and cirrhosis. BAY 41-2272 is a canonical non-nitric oxide (NO)-based soluble guanylyl cyclase (sGC) stimulator that triggers cyclic guanosine monophosphate (cGMP) signaling for attenuation of fibrotic disorders; however, the impact of BAY 41-2272 on HSC activation remains ill-defined. Transforming growth factor (TGF)β and its downstream connective tissue growth factor (CTGF or cellular communication network factor 2, CCN2) are critical fibrogenic cytokines for accelerating HSC activation. Here, we identified that BAY 41-2272 significantly inhibited the TGFβ1-induced mRNA and protein expression of CTGF in mouse primary HSCs. Indeed, BAY 41-2272 increased the sGC activity and cGMP levels that were potentiated by two NO donors and inhibited by a specific sGC inhibitor, ODQ. Surprisingly, the inhibitory effects of BAY 41-2272 on CTGF expression were independent of the sGC/cGMP pathway in TGFβ1-activated primary HSCs. BAY 41-2272 selectively restricted the TGFβ1-induced phosphorylation of Akt but not canonical Smad2/3 in primary HSCs. Together, we illustrate a unique framework of BAY 41-2272 for inhibiting TGFβ1-induced CTGF upregulation and HSC activation via a noncanonical Akt-dependent but sGC/cGMP-independent pathway. |
topic |
Akt BAY 41-2272 CTGF hepatic stellate cell sGC |
url |
https://www.mdpi.com/2227-9059/8/9/330 |
work_keys_str_mv |
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