Vericiguat-induced enhancement of mitochondrial function dependent on cGMP levels in human cardiac fibroblasts.

Low dose cyclase soluble guanylyl (sGC) stimulation has shown to have direct antifibrotic effects, improving myocardial remodeling in the absence of hemodynamic effects in heart failure (HF) patients. The aim was to study the effect of vericiguat, an oral stimulator of sGC independently of nitric oxide, on mitochondrial function and oxidative stress in an in vitro study under pro-inflammatory conditions, simulating HF conditions. Human Cardiac Fibroblasts (HCF) cellular line was incubated in absence (Control-group) and presence of TNF-α (50 ng/ml) (TNF-group). 30 μΜ of vericiguat was added after 24h TNF-α incubation (50 ng/ml) (TNF+Ver-group). cGMP levels, mitochondrial membrane potential (∆Ψm), superoxide dismutase 2 (SOD2) expression and reactive oxygen species (ROS) production were measured. Results represent mean±SEM of six experiments/group. Results confirmed increased cGMP production induced by vericiguat. ∆Ψm was significantly reduced under pro-inflammatory conditions. Vericiguat increased mitochondrial function, reverting effect induced by TNF-α (∆Ψm (Fluorescence units): control-group:25.90±0.90 vs TNF-group:5.80±0.30;p=0.001;TNF+Ver-group:10.50±1.00;p=0.009 respect to TNF-group). ROS production was found significantly increased in the TNF-group compared to control-group, vericiguat significantly reduced ROS production. (ROS production (arbitrary densitometric units): control-group:0.64±0.03 vs TNF-group:1.69±0.20;p<0,001;TNF+Ver-group:0.76±0.02;p<0.001 respect to TNF-group). SOD2 expression was significantly higher in the TNF-group compared to control and TNF+Ver-groups (SOD2 expression (arbitrary densitometric units): control-group:239.60±21.40 vs TNF-group:365.30±7.80;p<0,001;TNF+Ver-group:321.80±19.70;p=0.038 respect to TNF-group). Interestingly, a positive correlation was found between cGMP levels and ∆Ψm in HCF (Rho Spearman=0.850;p=0.010). It was not observed between cGMP and ROS or SOD2. As conclusion, vericiguat improved mitochondrial function in a cGMP level-dependent manner in HCF under pro-inflammatory conditions.