Sodium Thiosulfate acts as an H2S mimetic to prevent intimal hyperplasia via inhibition of tubulin polymerization
Authors: Macabrey Diane , Longchamp Alban , MacArthur Michael R. , Lambelet Martine , Urfer Severine , Corpataux Jean-Marc , Deglise Sebastien , Allagnat Florent 
Published: September 2021

AbstractBackgroundIntimal hyperplasia (IH) remains a major limitation in the long-term success of any type of revascularization. IH is due to vascular smooth muscle cell (VSMC) dedifferentiation, proliferation and migration. The gasotransmitter Hydrogen Sulfide (H2S) inhibits IH in pre-clinical models. However, there is currently no clinically approved H2S donor. Here we used sodium thiosulfate (STS), a clinically-approved source of sulfur, to limit IH.MethodsHypercholesterolemic LDLR deleted (LDLR-/-), WT or CSE-/-male mice randomly treated with 4g/L STS in the water bottle were submitted to focal carotid artery stenosis to induce IH. Human vein segments were maintained in culture for 7 days to induce IH. Furtherin vitrostudies were conducted in primary human vascular smooth muscle cell (VSMC).FindingsSTS inhibited IH in mice and in human vein segments. STS inhibited cell proliferation in the carotid artery wall and in human vein segments. STS increased polysulfidesin vivoand protein persulfidationin vitro, which correlated with microtubule depolymerization, cell cycle arrest and reduced VSMC migration and proliferation.InterpretationSTS, a drug used for the treatment of cyanide poisoning and calciphylaxis, protects against IH in a mouse model of arterial restenosis and in human vein segments. STS acts as an H2S donor to limit VSMC migration and proliferation via microtubule depolymerization.FundingThis work was supported by the Swiss National Science Foundation (grant FN-310030_176158 to FA and SD and PZ00P3-185927 to AL); the Novartis Foundation to FA; and the Union des Sociétés Suisses des Maladies Vasculaires to SD.Graphical AbstractResearch in contextEvidence before this studyIntimal hyperplasia (IH) is a complex process leading to vessel restenosis, a major complication following cardiovascular surgeries and angioplasties. Therapies to limit IH are currently limited. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, limits restenosis. However, despite these potent cardiovascular benefits in pre-clinical studies, H2S-based therapeutics are not available yet. Sodium thiosulfate (Na2S2O3) is an FDA-approved drug used for the treatment of cyanide poisoning and calciphylaxis, a rare condition of vascular calcification affecting patients with end-stage renal disease. Evidence suggest that thiosulfate may generate H2Sin vivoin pre-clinical studies.Added value of this studyHere, we demonstrate that STS inhibit IH in a surgical mouse model of IH and in anex vivomodel of IH in human vein culture. We further found that STS increases circulating polysulfide levelsin vivoand inhibits IH via decreased cell proliferation via disruption of the normal cell’s cytoskeleton. Finally, using CSE knockout mice, the main enzyme responsible for H2S production in the vasculature, we found that STS rescue these mice from accelerated IF formation.Implications of all the available evidenceThese findings suggest that STS holds strong translational potentials to limit IH following vascular surgeries and should be investigated further.