Hydropersulfides (RSSH) Outperform Post-Conditioning and Other Reactive Sulfur Species in Limiting Ischemia–Reperfusion Injury in the Isolated Mouse Heart

Hydrogen sulfide (H₂ S) exhibits protective effects in cardiovascular disease such as my-ocardial ischemia/reperfusion (I/R) injury, cardiac hypertrophy, and atherosclerosis. Despite these findings, its mechanism of action remains elusive. Recent studies suggest that H₂ S can modulate protein activity through redox-based post-translational modifications of protein cysteine residues forming hydropersulfides (RSSH). Furthermore, emerging evidence indicates that reactive sulfur species, including RSSH and polysulfides, exhibit cardioprotective action. However, it is not clear yet whether there are any pharmacological differences in the use of H₂ S vs. RSSH and/or polysul-fides. This study aims to examine the differing cardioprotective effects of distinct reactive sulfur species (RSS) such as H₂ S, RSSH, and dialkyl trisulfides (RSSSR) compared with canonical ischemic post-conditioning in the context of a Langendorff ex-vivo myocardial I/R injury model. For the first time, a side-by-side study has revealed that exogenous RSSH donation is a superior approach to maintain post-ischemic function and limit infarct size when compared with other RSS and mechanical post-conditioning. Our results also suggest that RSSH preserves mitochondrial respiration in H9c2 cardiomyocytes exposed to hypoxia-reoxygenation via inhibition of oxidative phosphorylation while preserving cell viability.