Beneficial effect of Vericiguat on mitochondrial function and oxidative stress in human cardiac microvascular endothelial cells. In vitro study

Vericiguat is a soluble guanylate cyclase (sGC) stimulator, which, in addition to vasodilatory optimal medical treatment for heart failure (HF), reduced incidence of cardiovascular death and HF hospitalization, suggesting additional effects to vascular vasodilatation. The aim was to study effect of vericiguat on mitochondrial function and oxidative stress in an in vitro study under pro-inflammatory conditions, simulating HF conditions. Human cardiac microvascular endothelial cell line (HCMEC) 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), gp91phox NADPH-subunit expression and reactive oxygen species (ROS) production were measured by Western blot and commercial kits. Results are represented as mean±SEM of six experiments for each experimental group. Results confirmed increased cGMP production induced by vericiguat addition. Interestingly, the mitochondria function marker ∆Ψm was significantly reduced in HCMEC incubated with TNF-α respect to control-group, but vericiguat reverted effect induced by TNF-α (∆Ψm (Fluorescence units): control-group:2.21±0.14 vs TNF-group:0.56±0.03;p<0.001;TNF+Ver-group:1.35±0.06;p<0.001 respect to TNF-group). Expression of pro-oxidative gp91phox protein and ROS production were significantly increased in HCMEC incubated with TNF-α compared to control, however, vericiguat reduced gp91phox and ROS levels to similar values found in the control group (gp91phox expression (arbitrary densitometric units):control-group:8.50±1.50 vs TNF-group:147.30±10.90;p<0.001; TNF+Ver-group:10.96±1.19;p=0.001 respect to TNF-group; ROS production (arbitrary densitometric units):control-group:1.52±0.07 vs TNF-group:2.51±0.08;p<0,001;TNF+Ver-group:1.53±0.09;p<0.001 respect to TNF-group). As conclusion, vericiguat improved mitochondrial function and reduced oxidative stress in HCMEC under pro-inflammatory conditions, suggesting beneficial effects on cellular function in addition to stimulate cGMP production.