Discovery of a Novel COS/H2S-Donor Hybridized sGC Stimulator for Alleviating Isoproterenol-Induced Myocardial Fibrosis

Abstract

Myocardial fibrosis contributes to heart failure (HF) progression, which is associated with impaired nitric oxide (NO)–soluble guanylyl cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling. Hydrogen sulfide (H₂S), a cardioprotective gasotransmitter, is reduced in patients with HF. Therapeutic options targeting both sGC activation and H₂S enhancement remain limited. We have developed a novel carbonyl sulfide (COS)/H₂S-donor hybrid sGC stimulator, COS-A, which exhibits a well-characterized H₂S-releasing property. Compound COS-A outperformed vericiguat in sGC activation in vitro and reduced fibrosis in transforming growth factor-beta 1 (TGF-β1)-treated cardiac fibroblasts by increasing cGMP and H₂S levels. In isoproterenol (ISO)-induced HF mice, COS-A improved cardiac function comparably to vericiguat. Histological findings revealed its antifibrotic effects through sGC activation and elevation of H₂S. Our findings indicate that this COS/H₂S-donor hybridized sGC stimulator holds therapeutic promise for HF treatment.