Soluble Guanylate Cyclase Stimulator Vericiguat Attenuates Angiotensin II-Induced Oxidative Stress and Cardiac Remodeling.

Abstract

Background: Vericiguat, an oral soluble guanylate cyclase stimulator, is a novel therapeutic agent for patients with heart failure with reduced ejection fraction; however, the detailed cardioprotective mechanism remains unclear. We aimed to explore the mechanism of the effect of vericiguat on the myocardium, particularly focusing on oxidative stress, using in vivo and in vitro experiments.

Methods and results: Male 8-week-old mice were divided into a control group, angiotensin II (AngII) infusion group, and AngII infusion with low- or high-dose vericiguat treatment group. After 14 days of treatment, vericiguat did not affect the systolic or diastolic blood pressure increase caused by AngII infusion. AngII-induced cardiac hypertrophy and fibrosis in the left ventricle (LV) were significantly ameliorated by high-dose vericiguat treatment. AngII-induced O₂^-overproduction and upregulation of messenger RNA levels of Nppa, Nppb, Myh7, Col1a1, Col3A1, and Tgfb1 in the LV were significantly attenuated by vericiguat in a dose-dependent manner. Incubation of neonatal rat cardiomyocytes using vericiguat and AngII revealed that preceding incubation with vericiguat directly reduced AngII-induced cardiomyocyte O₂^-production and cardiac hypertrophy-associated gene expression. In addition, AngII-induced phosphorylation of ERK 1/2 or p38 MAPK was significantly attenuated by the incubation with vericiguat.

Conclusions: Our study demonstrated that vericiguat suppresses myocardial oxidative stress via the regulation of ERK 1/2 or p38 MAPK signaling, leading to antihypertrophic/fibrotic effects.