A soluble guanylate cyclase stimulator affects hepatic metabolic and redox states in a rat model of early-stage HFpEF
X Vazquez-Abuin, S Morana-Fernandez, A Aragon-Herrera, V Serrano-Cruz, P Sandner, S B Bravo, A Rodrigues, A Goncalves, J Pereira Morais, I N Alves, C Sousa-Mendes, I Falcao-Pires, J R Gonzalez-Juanatey, S Feijoo-Bandin, F LagoAbstract
Introduction
Heart failure with preserved ejection fraction (HFpEF) is a systemic cardiometabolic syndrome characterised by endothelial dysfunction and impaired nitric oxide (NO) signalling, in which the liver is frequently affected, particularly in the presence of metabolic syndrome. Targeting the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) signalling pathway represents a promising yet underexplored therapeutic strategy in liver disease. While soluble guanylate cyclase (sGC) stimulators have demonstrated beneficial cardiovascular effects, their impact on hepatic function and molecular regulation remains incompletely understood.
Purpose
This study aimed to investigate the effects of pharmacological sGC stimulation on the HepG2 cell line and on liver tissue in a preclinical rat model of early-stage HFpEF associated with metabolic syndrome, with a particular focus on alterations in hepatic proteome profile.
Methods
Male Zucker fatty and spontaneously hypertensive (ZSF1) rats were randomised into groups (n=10): lean group, obese control group, and obese treated group during 4 weeks with sGC stimulator (3 mg/kg/p.o daily). Proteomic profiling on liver tissue samples was performed on a TripleTOF® 6600 LC-MS/MS system. Human hepatoma HepG2 cells were exposed to sGC stimulator with or without palmitic acid to induce mitochondrial damage. Cell viability (MTT), reactive oxygen species (ROS), glucose consumption, and glutathione (GSH/GSSG) levels were assessed using commercial kits.
Results
sGC stimulator treatment induced significant alterations in the hepatic proteomic profile of obese ZSF1 rats compared with obese controls, without affecting overall liver weight or morphology. Quantitative proteomic analysis comparing the obese treated group with the obese control group identified 55 hepatic proteins with significantly altered expression levels. From these, we selected 29 proteins associated with lipid and glucose metabolism, insulin sensitivity, steatosis, oxidative stress, fibrosis, cirrhosis and associated with mitochondrial function, based on the evidence previously described in literature. Proteins associated with antioxidant process and metabolic regulation were upregulated, whereas proteins linked to steatosis and fibrotic remodelling were downregulated.
Conclusions
Our findings indicate that sGC stimulator treatment modulates hepatic molecular pathways in an animal model of HFpEF associated with metabolic syndrome when administered at an early-stage of disease. These findings suggest that sGC stimulation may exert beneficial extra-cardiac effects, partially normalising metabolic, oxidative, and mitochondrial alterations and providing novel insights into the hepatic actions of sGC beyond the cardiovascular system.Figure