H₂S mediates the protective roles of polysulfides against lipopolysaccharide-induced vascular smooth muscle cell dysfunctions

Abstract

Hydrogen sulfide (H₂S), a gaseous signaling molecule, exerts protective effects in cardiovascular and inflammatory diseases. Polysulfides (e.g., Na₂S₂, Na₂S₃, Na₂S₄), as reactive sulfur species, exhibit unique redox behavior and may serve as slow-releasing H2S donors. Lipopolysaccharide (LPS), a potent endotoxin from Gram-negative bacteria, induces vascular inflammation and smooth muscle cell (SMC) dysfunction, contributing to sepsis-associated cardiovascular complications. Yet the roles of polysulfides in LPS-induced SMC dysfunctions remain unclear. This study evaluated the H₂S-releasing capacities of these polysulfides and their impact on LPS-induced alterations in mouse SMCs. Utilizing biochemical assays and cell imaging techniques, we found that H₂S can be spontaneously released from Na₂S₂, and this release can be significantly enhanced in the presence of cysteine. Both Na₂S₂ and NaHS (a well-known H₂S-releasing donor) inhibited the growth of both Gram-negative and Gram-positive bacteria. Also, we discovered that LPS treatment (10 ng/mL) induced SMC proliferation, oxidative stress, and upregulation of pro-inflammatory genes (IL-2, IL-4, TNF-α). Notably, Na₂S₂ elevated intracellular H₂S levels and reversed LPS-induced functional and inflammatory changes in SMCs. These findings highlight Na₂S₂ as a bioactive, thiol-sensitive H₂S donor capable of mitigating LPS-induced vascular inflammation and SMC dysfunctions.