Vericiguat promotes preservation of mitophagy and mitochondrial function in human cardiac myocytes. In vitro study

Vericiguat, a soluble guanylate cyclase stimulator, provides additional benefits to standard treatment against heart failure (HF). It is known that decreased mitochondrial function and/or deficient process to selectively remove damaged mitochondria (mitophagy) in cardiac cells are crucial in HF progression. The aim was to study vericiguat effect on mitophagy and mitochondrial function in an in vitro study under pro-inflammatory conditions, simulating HF conditions. Human Cardiac Myocytes (HCM) were 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). Expression levels of proteins closely involved in mitophagy Pink-1 and Parkin, cGMP production and mitochondrial function (∆Ψm) were analyzed using Dot-blot and commercial kits. Results represent mean±SEM of six experiments/group. Results confirmed increased cGMP production induced by vericiguat. ∆Ψm was reduced in HCM incubated with TNF-α respect to control-group, vericiguat addition reverted the decreasing ∆Ψm induced by TNF-α (∆Ψm (Fluorescence units): control-group:2.30±0.11 vs TNF-group:0.98±0.02;p<0.001;TNF+Ver-group:1.28±0.04;p<0.001 respect to TNF-group). Expression of Pink-1 and Parkin were found significantly decreased in TNF-group compared to control-group, however, Pink-1 and Parkin expression in the TNF+Ver-group showed similar values to them found in the control group (Pink-1 expression (arbitrary densitometric units):control-group:322.52±3.41 vs TNF-group:92.21±1.67;p<0.040;TNF+Ver-group:289.50±3.07;p=0.001 respect to TNF-group; Parkin expression (arbitrary densitometric units):control-group:251.54±2.18 vs TNF-group:102.82±1.23;p=0.004;TNF+Ver-group:288.01±3.08;p=0.002 respect to TNF-group). Significant positive correlation was found between mitophagy related proteins expression and cGMP levels in HCM. As conclusion, vericiguat improved mitochondrial function in HCM under pro-inflammatory conditions, which may be explained by preservation of mitophagy in a cGMP level-dependent manner.