Methods: Thirty-six adult male Wistar rats were randomized into six groups: control, doxorubicin induction, doxorubicin plus vericiguat 0.5 mg/kg, doxorubicin plus vericiguat 1 mg/kg, doxorubicin plus vericiguat 2 mg/kg, and vericiguat safety group. Doxorubicin was administered intraperitoneally at 1 mg/kg twice weekly for six weeks, reaching a cumulative dose of 12 mg/kg. Vericiguat was administered orally once daily for four weeks. Serum nitrite, as an indirect index of NO bioavailability, together with cGMP, Bax, Bcl-2, Bax/Bcl-2 ratio, and NT-proBNP were assessed by assay-based methods, while myocardial PRKG1 and PRKG2 protein expression was evaluated by western blotting. Data were analyzed using one-way ANOVA followed by LSD post hoc test.
Results: Doxorubicin markedly reduced serum nitrite and cGMP levels, suppressed myocardial PRKG1 and PRKG2 expression, increased Bax, decreased Bcl-2, and elevated the Bax/Bcl-2 ratio, indicating impairment of NO–sGC–cGMP–PRKG signaling and a shift toward pro-apoptotic toxicity. Vericiguat partially restored NO-related bioavailability, with the 2 mg/kg dose increasing serum nitrite from 9.29 ± 1.61 to 15.40 ± 1.68 µmol/L. Vericiguat produced a dose-dependent pharmacological restoration of cGMP, with the 2 mg/kg dose increasing cGMP from 0.81 ± 0.06 to 1.86 ± 0.13 pmol/mL. PRKG1 expression increased from 0.30 ± 0.10 in the doxorubicin group to 0.83 ± 0.01 after vericiguat 2 mg/kg, while PRKG2 expression increased from 0.24 ± 0.01 to 0.65 ± 0.05. Vericiguat also attenuated apoptotic vulnerability by reducing Bax from 127.2 ± 5.81 to 90.82 ± 10.45 pg/mL, increasing Bcl-2 from 29.5 ± 4.97 to 68.17 ± 4.26 pg/mL, and lowering the Bax/Bcl-2 ratio from 3.06 ± 0.35 to 1.32 ± 0.14. Reduction of NT-proBNP further supported attenuation of doxorubicin-induced myocardial stress. The vericiguat-only group showed no evidence of adverse apoptotic or signaling disruption.
Conclusion: Vericiguat mitigated doxorubicin-induced cardiotoxic injury through restoration of NO–sGC–cGMP–PRKG signaling and rebalancing of Bax/Bcl-2-defined apoptotic vulnerability. These findings support vericiguat as a pharmacologically plausible and toxicologically tolerable candidate for further investigation against anthracycline-related myocardial injury.