Nitric oxide and carbon monoxide antagonize TGF-β through ligand-independent internalization of TβR1/ALK5

Hovater, Michael B.; Ying, Wei‐Zhong; Agarwal, Anupam; Sanders, Paul W.

doi:10.1152/ajprenal.00353.2014

Cited by 12 publications

(10 citation statements)

References 61 publications

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“…Moreover, it has been reported that HMOX-1 derived metabolites including CO activated the mitochondrial function of astrocytes via HIF-1α/estrogen-related receptor α (ERRα) circuit and therefore play an important role in the repair of neurovascular function after ischemic brain injury [65]. Additionally, CO has been suggested as a protective factor limiting the profibrotic effects of TGF-β in the vasculature [66]. The components of HMOX-1/CO pathway have been shown in hepatocellular carcinoma cells to confer their resistance to TGF-β-mediated growth inhibition by increasing Smad3 phosphorylation via the ERK1/2 pathway [67].…”

Section: Discussionmentioning

confidence: 99%

Evidence for Cytoprotective Effect of Carbon Monoxide Donor in the Development of Acute Esophagitis Leading to Acute Esophageal Epithelium Lesions

Magierowska

Bakalarz

Wójcik

et al. 2020

Cells

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Exposure to acidic gastric content due to malfunction of lower esophageal sphincter leads to acute reflux esophagitis (RE) leading to disruption of esophageal epithelial cells. Carbon monoxide (CO) produced by heme oxygenase (HMOX) activity or released from its donor, tricarbonyldichlororuthenium (II) dimer (CORM-2) was reported to protect gastric mucosa against acid-dependent non-steroidal anti-inflammatory drug-induced damage. Thus, we aimed to investigate if CO affects RE-induced esophageal epithelium lesions development. RE induced in Wistar rats by the ligation of a junction between pylorus and forestomach were pretreated i.g. with vehicle CORM-2; RuCl3; zinc protoporphyrin IX, or hemin. CORM-2 was combined with NG-nitro-L-arginine (L-NNA), indomethacin, capsazepine, or capsaicin-induced sensory nerve ablation. Esophageal lesion score (ELS), esophageal blood flow (EBF), and mucus production were determined by planimetry, laser flowmetry, histology. Esophageal Nrf-2, HMOXs, COXs, NOSs, TNF-α and its receptor, IL-1 family and IL-1 receptor antagonist (RA), NF-κB, HIF-1α, annexin-A1, suppressor of cytokine signaling (SOCS3), TRPV1, c-Jun, c-Fos mRNA/protein expressions, PGE2, 8-hydroxy-deoxyguanozine (8-OHdG) and serum COHb, TGF-β1, TGF-β2, IL-1β, and IL-6 content were assessed by PCR, immunoblotting, immunohistochemistry, gas chromatography, ELISA or Luminex platform. Hemin or CORM-2 alone or combined with L-NNA or indomethacin decreased ELS. Capsazepine or capsaicin-induced denervation reversed CORM-2 effects. COHb blood content, esophageal HMOX-1, Nrf-2, TRPV1 protein, annexin-A1, HIF-1α, IL-1 family, NF-κB, c-Jun, c-Fos, SOCS3 mRNA expressions, and 8-OHdG levels were elevated while PGE2 concentration was decreased after RE. CO donor-maintained elevated mucosal TRPV1 protein, HIF-1 α, annexin-A1, IL-1RA, SOCS3 mRNA expression, or TGF-β serum content, decreasing 8-OHdG level, and particular inflammatory markers expression/concentration. CORM-2 and Nrf-2/HMOX-1/CO pathway prevent esophageal mucosa against RE-induced lesions, DNA oxidation, and inflammatory response involving HIF-1α, annexin-A1, SOCS3, IL-1RA, TGF-β-modulated pathways. Esophagoprotective and hyperemic CO effects are in part mediated by afferent sensory neurons and TRPV1 receptors activity with questionable COX/PGE2 or NO/NOS systems involvement.

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Section: Discussionmentioning

confidence: 99%

Evidence for Cytoprotective Effect of Carbon Monoxide Donor in the Development of Acute Esophagitis Leading to Acute Esophageal Epithelium Lesions

Magierowska

Bakalarz

Wójcik

et al. 2020

Cells

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“…GDNF is a member of the TGFβ superfamily and we found that it could induce HSC activation. TGFβ is mediating its multifunctional effects on liver cells by binding to ALK5 39, 40 followed by subsequent downstream signalling via phosphorylation and nuclear translocation of Smad2/3 to regulate target gene expression in a context-dependent manner. 41 Thus, we hypothesised that GDNF might involve ALK5 to induce HSC activation.…”

Section: Discussionmentioning

confidence: 99%

Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling

Le¹,

et al. 2019

Gut

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ObjectiveAlthough glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-β superfamily, its function in liver fibrosis has rarely been studied. Here, we investigated the role of GDNF in hepatic stellate cell (HSC) activation and liver fibrosis in humans and mice.DesignGDNF expression was examined in liver biopsies and sera from patients with liver fibrosis. The functional role of GDNF in liver fibrosis was examined in mice with adenoviral delivery of the GDNF gene, GDNF sgRNA CRISPR/Cas9 and the administration of GDNF-blocking antibodies. GDNF was examined on HSC activation using human and mouse primary HSCs. The binding of activin receptor-like kinase 5 (ALK5) to GDNF was determined using surface plasmon resonance (SPR), molecular docking, mutagenesis and co-immunoprecipitation.ResultsGDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with α-smooth muscle actin (α-SMA) and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signalling inhibition by GDNF-blocking antibodies have reduced fibrosis and HSC activation. GDNF is confined mainly to HSCs and contributes to HSC activation through ALK5 at His39 and Asp76 and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRα1). GDNF, ALK5 and α-SMA colocalise in human and mouse HSCs, as demonstrated by confocal microscopy.ConclusionsGDNF promotes HSC activation and liver fibrosis through ALK5/Smad signalling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.

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“…downregulated gastric mucosal mRNA expression for anti-inflammatory Anxa1 , upregulated mucosal mRNA expression for Tgfbr2 and r3 and maintained elevated TGFB1 and TGFB2 serum concentration in rats administered with ethanol. It has been previously reported that CORM-2 can antagonize TGFB activity through internalization of TGFB receptor 1 (ALK5) inhibiting profibrotic effect of this inflammatory factor 102 . However, we observed that Anxa1 mRNA expression was decreased in rats administered with high dose of aspirin but pretreatment with BW-CO-111 increased the gastric mucosal mRNA expression for this protein and similarly to rats administered with ethanol, this CO-prodrug maintained elevated TGFB1 and TGFB2 serum contents and maintained upregulated mucosal mRNA expression for Tgfbr3 by aspirin.…”

Section: Discussionmentioning

confidence: 99%

Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage

Bakalarz

Surmiak

Yang

et al. 2021

Acta Pharmaceutica Sinica B

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Metal-based carbon monoxide (CO)-releasing molecules have been shown to exert anti-inflammatory and anti-oxidative properties maintaining gastric mucosal integrity. We are interested in further development of metal-free CO-based therapeutics for oral administration. Thus, we examine the protective effect of representative CO prodrug, BW-CO-111, in rat models of gastric damage induced by necrotic ethanol or aspirin, a representative non-steroidal anti-inflammatory drug. Treatment effectiveness was assessed by measuring the microscopic/macroscopic gastric damage area and gastric blood flow by laser flowmetry. Gastric mucosal mRNA and/or protein expressions of HMOX1, HMOX2, nuclear factor erythroid 2-related factor 2, COX1, COX2, iNos , Anxa1 and serum contents of TGFB1, TGFB2, IL1B, IL2, IL4, IL5, IL6, IL10, IL12, tumor necrosis factor α , interferon γ , and GM-CSF were determined. CO content in gastric mucosa was assessed by gas chromatography. Pretreatment with BW-CO-111 (0.1 mg/kg, i.g.) increased gastric mucosal content of CO and reduced gastric lesions area in both models followed by increased GBF. These protective effects of the CO prodrug were supported by changes in expressions of molecular biomarkers. However, because the pathomechanisms of gastric damage differ between topical administration of ethanol and aspirin, the possible protective and anti-inflammatory mechanisms of BW-CO-111 may be somewhat different in these models.

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Nitric oxide and carbon monoxide antagonize TGF-β through ligand-independent internalization of TβR1/ALK5

Cited by 12 publications

References 61 publications

Evidence for Cytoprotective Effect of Carbon Monoxide Donor in the Development of Acute Esophagitis Leading to Acute Esophageal Epithelium Lesions

Evidence for Cytoprotective Effect of Carbon Monoxide Donor in the Development of Acute Esophagitis Leading to Acute Esophageal Epithelium Lesions

Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling

Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage

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