Abstract
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.
Highlights
The overwhelming activation and proliferation of hepatic stellate cells (HSCs) is an important factor in hepatic fibrosis, an advanced pathogenic condition in liver cirrhosis, portal hypertension, and hepatocellular carcinoma
To evaluate the biological significance of soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling in primary HSCs, we first evaluated the effect of a typical sGC stimulator BAY 41-2272 on TGFβ1-induced connective tissue growth factor (CTGF) expression that is a critical pro-fibrotic cytokine for HSC activation
The TGFβ1-induced proliferation of primary HSCs was significantly restricted by BAY 41-2272 (10 μM; Figure 1C), suggesting that the compound may serve as an agent to ameliorate HSC activation
Summary
The overwhelming activation and proliferation of hepatic stellate cells (HSCs) is an important factor in hepatic fibrosis, an advanced pathogenic condition in liver cirrhosis, portal hypertension, and hepatocellular carcinoma. The TGFβ-induced activation of HSCs during liver fibrosis takes place via canonical Smad-dependent or noncanonical Smad-independent signaling such as the Akt pathway [18,19]. The pro-fibrotic CTGF is upregulated and promotes the pathogenic process of liver fibrosis including cell proliferation, contractility, migration, and ECM production in activated HSCs [21,22,23]. BAY 41-2272 alternatively inhibited the noncanonical Akt instead of canonical Smad2/3 pathway in TGFβ1-primed HSCs. Our findings provide a mechanistic basis for BAY 41-2272 activity as a potential agent for Akt-dependent inhibition of TGFβ1-instigated CTGF induction and HSC activation that is distinct from the canonical sGC/cGMP and Smad signaling
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