Soluble guanylate cyclase stimulator reduced the gastrointestinal fibrosis in bleomycin-induced mouse model of systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undetermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90 % of patients. Soluble guanylate cyclase (sGC) stimulator is used to treat pulmonary artery hypertension (PAH) and has been shown to inhibit experimental skin fibrosis. Methods Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract was analyzed by real-time PCR, and the levels of collagen in the tissue were measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [dyeing distance × (duodenum − appendix)] − 1 × 100 (%). We treated BLM-treated mice with sGC stimulator or DMSO orally and analyzed them on day 42. Results Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal hyperproliferative and prefibrotic response in C57BL/6J mice. In addition, the gene expression levels of Col3a1, CCN2, MMP-2, MMP-9, TIMP-1, and TIMP-2 in the esophagus were significantly increased in BLM-treated mice. More severe hyperproliferative and prefibrotic response was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC stimulator treatment significantly reduced hyperproliferative and prefibrotic response of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay. Conclusions These findings suggest that BLM induces gastrointestinal hyperproliferative and prefibrotic response in C57BL/6J mice, and treatment with sGC stimulator improves the BLM-induced gastrointestinal lesion.

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Soluble Guanylate Cyclase Reduced the Gastrointestinal Fibrosis in Bleomycin-induced Mouse Model of Systemic Sclerosis.

10.21203/rs.3.rs-138442/v1 ◽

2021 ◽

Author(s):

Yuzuru Yamamoto ◽

Takaichi Okano ◽

Hirotaka Yamada ◽

Kengo Akashi ◽

Sho Sendo ◽

...

Keyword(s):

Systemic Sclerosis ◽

Gastrointestinal Tract ◽

Histological Examination ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Intestinal Transport ◽

Pulmonary Artery Hypertension ◽

Vascular Lesions ◽

Muscularis Mucosa ◽

Peristaltic Movement

Abstract Background: Systemic sclerosis (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90% of patients. Soluble guanylate cyclase (sGC) is used to treat pulmonary artery hypertension (PAH), and has been shown to inhibit experimental skin fibrosis.Methods: Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract were analyzed by real-time PCR, and the levels of collagen in the tissue was measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [Dyeing distance×(Duodenum- Appendix)] -1 ×100 (%). We treated BLM-treated mice with soluble guanylate cyclase (sGC) or DMSO orally and analyzed them on day 42.Results: Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal fibrosis in C57BL/6J mice. In addition, the levels of Col3a1 and CTGF were significantly increased in BLM-treated mice. More severe fibrosis was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC treatment significantly reduced fibrosis of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay. Conclusions: These findings suggest that BLM induces gastrointestinal fibrosis in C57BL/6J mice, and treatment with sGC improves the BLM-induced gastrointestinal lesion.

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SAT0283 SOLUBLE GUANYLATE CYCLASE REDUCED THE GASTROINTESTINAL FIBROSIS IN BLEOMYCIN-INDUCED MOUSE MODEL OF SYSTEMIC SCLEROSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2768 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1086.1-1086

Author(s):

Y. Yamamoto ◽

T. Okano ◽

T. Nagamoto ◽

Y. Fujikawa ◽

Y. Ichise ◽

...

Keyword(s):

Systemic Sclerosis ◽

Gastrointestinal Tract ◽

Histological Examination ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Skin Fibrosis ◽

Vascular Lesions ◽

Muscularis Mucosa ◽

Gastrointestinal Complications ◽

Peristaltic Movement

Background:Systemic scleroderma (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90% of patients1. Soluble guanylate cyclase (sGC) is used to treat pulmonary artery hypertension (PAH), and has been shown to inhibit experimental skin fibrosis2.Objectives:The aim of this study is to investigate whether bleomycin (BLM)-treated mice show gastrointestinal fibrosis, and find a therapeutic strategy to the lesion.Methods:Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract were analyzed by real-time PCR, and the levels of collagen in the tissue was measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [Dyeing distance×(Duodenum- Appendix)] -1 ×100 (%). We treated BLM-treated mice with soluble guanylate cyclase (sGC) or DMSO orally and analyzed them on day 42.Results:Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal fibrosis in C57BL/6J mice. In addition, the levels of Col3a1 and CTGF were significantly increased in BLM-treated mice. More severe fibrosis was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC treatment significantly reduced fibrosis of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay.Esophagus (Masson’s trichrome stain×100)* One way ANOVA Newman-KeulsConclusion:These findings suggest that BLM induces gastrointestinal fibrosis in C57BL/6J mice, and treatment with sGC improves the BLM-induced gastrointestinal lesion.References:[1]Anton Emmanuel. Current management of the gastrointestinal complications of systemic sclerosis. Nat Rev Gastroenterol Hepatol. 2016; 13: 461-472.[2]Clara Dees, et al. Stimulators of Soluble Guanylate Cyclase (sGC) Inhibit experimental Skin Fibrosis of Different Aetiologies. Ann Rheum Dis. 2015;74 (8): 1621-5.Acknowledgments: :None.Disclosure of Interests:None declared

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Stimulation of Soluble Guanylate Cyclase by Riociguat prevents Tobacco smoke-induced Pulmonary Hypertension in mice

Pneumologie ◽

10.1055/s-0032-1315498 ◽

2012 ◽

Vol 66 (06) ◽

Cited By ~ 2

Author(s):

A Pichl ◽

N Parajuli ◽

M Seimetz ◽

JP Stasch ◽

R Frey ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Guanylate Cyclase ◽

Tobacco Smoke ◽

Soluble Guanylate Cyclase ◽

Stimulation Of

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Faculty Opinions recommendation of A novel kinetic trap for NO release from cytochrome c': a possible mechanism for NO release from activated soluble guanylate cyclase.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1002730.195638 ◽

2003 ◽

Author(s):

Bruce Averill

Keyword(s):

Cytochrome C ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Kinetic Trap ◽

No Release

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Soluble Guanylate Cyclase Stimulators and Activators: Where are We and Where to Go?

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190730110600 ◽

2019 ◽

Vol 19 (18) ◽

pp. 1544-1557 ◽

Cited By ~ 6

Author(s):

Sijia Xiao ◽

Qianbin Li ◽

Liqing Hu ◽

Zutao Yu ◽

Jie Yang ◽

...

Keyword(s):

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Muscle Relaxation ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Smooth Muscle Relaxation ◽

Secondary Messenger ◽

Physiological Processes ◽

Cgmp Pathway ◽

Preclinical And Clinical Studies

Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy (DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease (SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in the near future.

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Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042)

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.0c02154 ◽

2021 ◽

Author(s):

Michael G. Hahn ◽

Thomas Lampe ◽

Sherif El Sheikh ◽

Nils Griebenow ◽

Elisabeth Woltering ◽

...

Keyword(s):

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Guanylate Cyclase Activator ◽

Cyclase Activator

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Current Modulation of Guanylate Cyclase Pathway Activity—Mechanism and Clinical Implications

Molecules ◽

10.3390/molecules26113418 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3418

Author(s):

Grzegorz Grześk ◽

Alicja Nowaczyk

Keyword(s):

Guanylate Cyclase ◽

Natriuretic Peptides ◽

Soluble Guanylate Cyclase ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Pharmacological Intervention ◽

First Line ◽

Phosphodiesterase Type ◽

Activity Mechanism

For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became an interesting target for pharmacological intervention. There are several possible options leading to an increase in cyclic guanosine monophosphate concentrations. The first one is related to the uses of analogues of natriuretic peptides. The second is related to increasing levels of natriuretic peptides by the inhibition of degradation. The third leads to an increase in cyclic guanosine monophosphate concentration by the inhibition of its degradation by the inhibition of phosphodiesterase type 5. The last option involves increasing the concentration of cyclic guanosine monophosphate by the additional direct activation of soluble guanylate cyclase. Treatment based on the modulation of guanylate cyclase function is one of the most promising technologies in pharmacology. Pharmacological intervention is stable, effective and safe. Especially interesting is the role of stimulators and activators of soluble guanylate cyclase, which are able to increase the enzymatic activity to generate cyclic guanosine monophosphate independently of nitric oxide. Moreover, most of these agents are effective in chronic treatment in heart failure patients and pulmonary hypertension, and have potential to be a first line option.

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