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

Abstract

Hydrogen sulfide (H2S) exhibits protective effects in cardiovascular disease such as myocardial ischemia/reperfusion (I/R) injury, cardiac hypertrophy, and atherosclerosis. Despite these findings, its mechanism of action remains elusive. Recent studies suggest that H2S 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 H2S vs. RSSH and/or polysulfides. This study aims to examine the differing cardioprotective effects of distinct reactive sulfur species (RSS) such as H2S, 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.

Cysteine hydropersulfide reduces lipid peroxidation and protects against myocardial ischaemia-reperfusion injury - Are endogenous persulfides mediators of ischaemic preconditioning?

“…2 C). Our results thus corroborate and extend previous findings that demonstrated persulfide-generating precursors to exhibit potent cardioprotective effects in an ex vivo [ 14 ] and in vivo murine model of myocardial IRI [ 13 ].…”

“…Yet, despite impressive cell-protective activities of hydropersulfides, few pharmacological and/or interventional mechanistic studies have been carried out to date in isolated organ systems or in vivo using precursors that give rise to RSSH [ 13 ]. This is particularly true for cardiovascular research, with one notable exception: a very recent study using isolated perfused hearts and cultured cardiomyocytes demonstrated that hydropersulfides outperform other reactive sulfur species (in particular reduced glutathione) in limiting IRI, possibly by virtue of their ability to preserve mitochondrial respiration [ 14 ].…”

Photochemical Release of Hydropersulfides

“…Small molecules that can efficiently generate RSSH under physiological conditions are important research tools for investigating their roles in cellular processes. , Several donor molecules have been developed that release RSSH in the presence of specific stimuli such as cellular thiols, reactive oxygen species (ROS), − pH, − and enzymes. − Interestingly, several recent studies show that pharmacological application of RSSH species can inhibit/prevent cellular damage resulting from oxidative/electrophilic stress. ,, However, many RSSH precursors suffer from limitations, including a lack of controllable release kinetics and electrophilic byproduct formation. The photochemical release of biomolecules from light-sensitive precursors has been a longstanding strategy in biological research as it offers both spatial and temporal control over the administration of effector species.…”

“…23−26 Interestingly, several recent studies show that pharmacological application of RSSH species can inhibit/prevent cellular damage resulting from oxidative/electrophilic stress. 7,15,27 However, many RSSH precursors suffer from limitations, including a lack of controllable release kinetics and electrophilic byproduct formation. The photochemical release of biomolecules from light-sensitive precursors has been a longstanding strategy in biological research as it offers both spatial and temporal control over the administration of effector species.…”

Reactive Sulfur Species (RSS) in Physiological and Pathological Conditions and in Therapy

“…An original paper by Pharoah et al addresses the cardioprotective role of various RSS precursors [ 2 ]. This study was performed on the Langendorff ex vivo myocardial ischemia/reperfusion (I/R) injury model.…”