BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells

Chen, Po‐Jen; Kuo, Liang Mou; Wu, Yuan-Hua; Chang, Yu‐Chia; Lai, Kuei Hung; Hwang, Tsong‐Long

doi:10.3390/biomedicines8090330

Cited by 12 publications

(7 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most in vitro studies on the role of heme on sGC function are focused on examining the role of prior heme oxidation (and loss from H-NOX) on the effectiveness of heme-dependent sGC agonists (Morbidelli et al, 2010;Chen et al, 2020). We attempted to address the NMR-based results shown above by testing whether an oxidant such as ODQ can interfere with the sGC stimulatory activity, after the BAY/sGC β1 complex has been allowed to form.…”

Section: Varying the Timing Of Heme Oxidation: Effect The Sgc Catalyt...mentioning

confidence: 99%

Mapping of the sGC Stimulator BAY 41-2272 Binding Site on H-NOX Domain and Its Regulation by the Redox State of the Heme

Makrynitsa

Argyriou²,

Zompra³

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Soluble guanylate cyclase (sGC) is the main receptor of nitric oxide (NO) and by converting GTP to cGMP regulates numerous biological processes. The β1 subunit of the most abundant, α1β1 heterodimer, harbors an N-terminal domain called H-NOX, responsible for heme and NO binding and thus sGC activation. Dysfunction of the NO/sGC/cGMP axis is causally associated with pathological states such as heart failure and pulmonary hypertension. Enhancement of sGC enzymatic function can be effected by a class of drugs called sGC “stimulators,” which depend on reduced heme and synergize with low NO concentrations. Until recently, our knowledge about the binding mode of stimulators relied on low resolution cryo-EM structures of human sGC in complex with known stimulators, while information about the mode of synergy with NO is still limited. Herein, we couple NMR spectroscopy using the H-NOX domain of the Nostoc sp. cyanobacterium with cGMP determinations in aortic smooth muscle cells (A7r5) to study the impact of the redox state of the heme on the binding of the sGC stimulator BAY 41-2272 to the Ns H-NOX domain and on the catalytic function of the sGC. BAY 41-2272 binds on the surface of H-NOX with low affinity and this binding is enhanced by low NO concentrations. Subsequent titration of the heme oxidant ODQ, fails to modify the conformation of H-NOX or elicit loss of the heme, despite its oxidation. Treatment of A7r5 cells with ODQ following the addition of BAY 41-2272 and an NO donor can still inhibit cGMP synthesis. Overall, we describe an analysis in real time of the interaction of the sGC stimulator, BAY 41-2272, with the Ns H-NOX, map the amino acids that mediate this interaction and provide evidence to explain the characteristic synergy of BAY 41-2272 with NO. We also propose that ODQ can still oxidize the heme in the H-NOX/NO complex and inhibit sGC activity, even though the heme remains associated with H-NOX. These data provide a more-in-depth understanding of the molecular mode of action of sGC stimulators and can lead to an optimized design and development of novel sGC agonists.

show abstract

Section: Varying the Timing Of Heme Oxidation: Effect The Sgc Catalyt...mentioning

confidence: 99%

Mapping of the sGC Stimulator BAY 41-2272 Binding Site on H-NOX Domain and Its Regulation by the Redox State of the Heme

Makrynitsa

Argyriou²,

Zompra³

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…BAY 41-2272, a soluble guanylate cyclase stimulator not based on NO, touches off cGMP signal to attenuate LF. A unique BAY 41-2272 framework for the inhibition of HSCs stimulation though a non-classical Akt-dependent but sGC/cGMP-independent signal [56] .…”

Section: Other Roles With Smad Signaling Pathwaymentioning

confidence: 99%

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Zheng

Yang

Luo

et al. 2022

Preprint

View full text Add to dashboard Cite

Liver fibrosis (LF) is a trauma repair process carried out by the liver in response to various acute and chronic liver injuries, featured by excessive proliferation as well as abnormal dismissal of extracellular matrix as the main pathological features, and its continuous development will deteriorate into cirrhosis, liver cancer as well as other illnesses. The occurrence of LF is closely related to Hepatic stellate cells (HSCs) stimulation, and intervention in HSCs proliferation is expected to reverse LF. Plant-based small molecule drugs have anti-LF effects, and their mechanisms of action are related to anti-inflammation, anti-oxidative stress, as well as inhibition of abnormal accumulation of extracellular matrix. Consequently, new agents for HSCs will be required to furnish a possible curative response. Small-molecule natural products might be attractive for LF therapy. That is because they not only have the effect against HSCs, but also have excellent qualities such as low toxic side effects and easy availability from the perspective of safety and cost. In this review, we provide an updated review of the signal transduction pathways involved in HSCs and small-molecule natural products targeting HSCs reported in the past 3 years at home and abroad, with the aim of providing new ideas for the development of plant-based small molecule drugs targeting HSCs to reverse LF.

show abstract

“…It has been reported that TGFβ induces the expression of CTGF through Smad and Stat3 signaling pathways in HSCs. In A-HSCs, the pro-fibrotic CTGF is also upregulated and promotes the pathogenetic processes of hepatic fibrosis, including cell proliferation, contractility, migration and ECM production [26]. A-HSCs release CTGF and other pro-fibrogenic factors which drive the deposition of ECM [27].…”

Section: Fibrogenic Cytokinesmentioning

confidence: 99%

Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation

et al. 2021

View full text Add to dashboard Cite

Hepatic fibrosis is characterized by the pathological accumulation of extracellular matrix (ECM) in the liver resulting from the persistent liver injury and wound-healing reaction induced by various insults. Although hepatic fibrosis is considered reversible after eliminating the cause of injury, chronic injury left unchecked can progress to cirrhosis and liver cancer. A better understanding of the cellular and molecular mechanisms controlling the fibrotic response is needed to develop novel clinical strategies. It is well documented that activated hepatic stellate cells (HSCs) is the most principal cellular players promoting synthesis and deposition of ECM components. In the current review, we discuss pathways of HSC activation, emphasizing emerging extra- and intra-cellular signals that drive this important cellular response to hepatic fibrosis. A number of cell types and external stimuli converge upon HSCs to promote their activation, including hepatocytes, liver sinusoidal endothelial cells, macrophages, cytokines, altered ECM, hepatitis viral infection, enteric dysbiosis, lipid metabolism disorder, exosomes, microRNAs, alcohol, drugs and parasites. We also discuss the emerging signaling pathways and intracellular events that individually or synergistically drive HSC activation, including TGFβ/Smad, Notch, Wnt/β-catenin, Hedgehog and Hippo signaling pathways. These findings will provide novel potential therapeutic targets to arrest or reverse fibrosis and cirrhosis.

show abstract

BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells

Cited by 12 publications

References 64 publications

Mapping of the sGC Stimulator BAY 41-2272 Binding Site on H-NOX Domain and Its Regulation by the Redox State of the Heme

Mapping of the sGC Stimulator BAY 41-2272 Binding Site on H-NOX Domain and Its Regulation by the Redox State of the Heme

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation

Contact Info

Product

Resources

About