The soluble guanylate cyclase stimulator IW‐1973 prevents inflammation and fibrosis in experimental non‐alcoholic steatohepatitis

Abstract

Background and PurposeNon‐alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome and is characterized by steatosis, inflammation and fibrosis. Soluble guanylate cyclase (sGC) stimulation reduces inflammation and fibrosis in experimental models of lung, kidney and heart disease. Here, we tested whether sGC stimulation is also effective in experimental NASH.Experimental ApproachNASH was induced in mice by feeding a choline‐deficient, l‐amino acid‐defined, high‐fat diet. These mice received either placebo or the sGC stimulator IW‐1973 at two different doses (1 and 3 mg·kg−1·day−1) for 9 weeks. IW‐1973 was also tested in high‐fat diet (HFD)‐induced obese mice. Steatosis, inflammation and fibrosis were assessed by Oil Red O, haematoxylin–eosin, Masson's trichrome, Sirius Red, F4/80 and α‐smooth muscle actin staining. mRNA expression was assessed by quantitative PCR. Levels of IW‐1973, cytokines and cGMP were determined by LC‐MS/MS, Luminex and enzyme immunoassay respectively.Key ResultsMice with NASH showed reduced cGMP levels and sGC expression, increased steatosis, inflammation, fibrosis, TNF‐α and MCP‐1 levels and up‐regulated collagen types I α1 and α2, MMP2, TGF‐β1 and tissue metallopeptidase inhibitor 1 expression. IW‐1973 restored hepatic cGMP levels and sGC expression resulting in a dose‐dependent reduction of hepatic inflammation and fibrosis. IW‐1973 levels were ≈40‐fold higher in liver tissue than in plasma. IW‐1973 also reduced hepatic steatosis and adipocyte hypertrophy secondary to enhanced autophagy in HFD‐induced obese mice.Conclusions and ImplicationsOur data indicate that sGC stimulation prevents hepatic steatosis, inflammation and fibrosis in experimental NASH. These findings warrant further evaluation of IW‐1973 in the clinical setting.

Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease

“…These results are consistent with antifibrotic effects reported for other sGC agonists as well as for other effectors of the cGMP pathway in the kidney and other organs (Sandner and Stasch, 2017). In addition to IW-1973's effects in the kidney, we have recently shown that IW-1973 has anti-inflammatory and antifibrotic activity in the liver in a model of nonalcoholic steatohepatitis at doses that do not affect blood pressure (Flores-Costa et al, 2018).…”

Soluble Guanylate Cyclase Stimulators and Activators

“…Treatment with the sGC stimulator BAY 41-8543 improved metabolic measures (weight gain, fat mass, diabetic phenotype) in a mouse diet-induced obesity (DIO) model (Hoffmann et al 2015). In a similar DIO model, treatment with the sGC stimulator praliciguat improved glucose tolerance and insulin sensitivity and lower triglycerides (Schwartzkopf et al 2018) Furthermore, olinciguat and praliciguat reduced fasting glucose in the ZSF1 model of diabetic nephropathy (Profy et al 2017;Masferrer et al 2016), and the sGC stimulator praliciguat reduced hepatic steatosis in an experimental NASH model (Flores-Costa et al 2017). The promising metabolic effects suggest evaluation of sGC stimulators in individuals with metabolic diseases including obesity, diabetes, hyperlipidemia, and metabolic syndrome, and NASH may be warranted.…”

Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit

“…Recently, we and others have demonstrated that modulation of cyclic guanosine-3′,5′-monophosphate (cGMP) exerts antiinflammatory and antifibrogenic effects in models of NASH and reduces portal pressure and fibrogenesis in cirrhotic rats (3)(4)(5). In these studies, small molecules with the ability to stimulate soluble guanylate cyclase (sGC), an enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cGMP, proved to be efficacious in the prevention as well as in the treatment of hepatic inflammation and fibrosis (3)(4)(5). In particular, using an optimized experimental model of NASH induced by a cholinedeficient L-amino acid-defined high-fat diet (CDAHFD) (6), we recently demonstrated that administration of the sGC stimulator praliciguat (PRL) delayed, in a dose-dependent manner, the development of liver inflammation and fibrosis (3).…”

“…In these studies, small molecules with the ability to stimulate soluble guanylate cyclase (sGC), an enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cGMP, proved to be efficacious in the prevention as well as in the treatment of hepatic inflammation and fibrosis (3)(4)(5). In particular, using an optimized experimental model of NASH induced by a cholinedeficient L-amino acid-defined high-fat diet (CDAHFD) (6), we recently demonstrated that administration of the sGC stimulator praliciguat (PRL) delayed, in a dose-dependent manner, the development of liver inflammation and fibrosis (3). In addition, Schwabl et al, using another sGC stimulator (riociguat), described reductions in portal hypertension and liver fibrosis in cholestatic (bile duct ligation) and toxic (carbon tetrachloride; CCl 4 ) models of cirrhosis in rats (4).…”