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Sodium Thiosulfate acts as an H2S mimetic to prevent intimal hyperplasia via inhibition of tubulin polymerization

Diane Macabrey, View ORCID ProfileAlban Longchamp, View ORCID ProfileMichael R. MacArthur, Martine Lambelet, Severine Urfer, Jean-Marc Corpataux, View ORCID ProfileSebastien Deglise, View ORCID ProfileFlorent Allagnat
doi: https://doi.org/10.1101/2021.09.09.459573
Diane Macabrey
1Department of Vascular Surgery, Lausanne University Hospital, Switzerland
2Department of Biomedical Sciences, University of Lausanne, Switzerland
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Alban Longchamp
1Department of Vascular Surgery, Lausanne University Hospital, Switzerland
2Department of Biomedical Sciences, University of Lausanne, Switzerland
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  • ORCID record for Alban Longchamp
Michael R. MacArthur
3Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
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  • ORCID record for Michael R. MacArthur
Martine Lambelet
1Department of Vascular Surgery, Lausanne University Hospital, Switzerland
2Department of Biomedical Sciences, University of Lausanne, Switzerland
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Severine Urfer
1Department of Vascular Surgery, Lausanne University Hospital, Switzerland
2Department of Biomedical Sciences, University of Lausanne, Switzerland
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Jean-Marc Corpataux
1Department of Vascular Surgery, Lausanne University Hospital, Switzerland
2Department of Biomedical Sciences, University of Lausanne, Switzerland
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Sebastien Deglise
1Department of Vascular Surgery, Lausanne University Hospital, Switzerland
2Department of Biomedical Sciences, University of Lausanne, Switzerland
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Florent Allagnat
1Department of Vascular Surgery, Lausanne University Hospital, Switzerland
2Department of Biomedical Sciences, University of Lausanne, Switzerland
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  • ORCID record for Florent Allagnat
  • For correspondence: Florent.allagnat@chuv.ch
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Abstract

Background Intimal 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.

Methods Hypercholesterolemic 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. Further in vitro studies were conducted in primary human vascular smooth muscle cell (VSMC).

Findings STS 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 polysulfides in vivo and protein persulfidation in vitro, which correlated with microtubule depolymerization, cell cycle arrest and reduced VSMC migration and proliferation.

Interpretation STS, 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.

Funding This 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.

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Evidence before this study Intimal 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 H2S in vivo in pre-clinical studies.

Added value of this study Here, we demonstrate that STS inhibit IH in a surgical mouse model of IH and in an ex vivo model of IH in human vein culture. We further found that STS increases circulating polysulfide levels in vivo and 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 evidence These findings suggest that STS holds strong translational potentials to limit IH following vascular surgeries and should be investigated further.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    CAS
    carotid artery stenosis
    H2S
    hydrogen sulfide
    IH
    intimal hyperplasia
    NaHS
    sodium hydrogen sulfur
    PCNA
    proliferating cell nuclear antigen
    SBP
    systolic blood pressure
    STS
    Sodium Thiosulfate
    VSMC
    vascular smooth muscle cells
    VGEL
    Van Gieson elastic lamina
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    Sodium Thiosulfate acts as an H2S mimetic to prevent intimal hyperplasia via inhibition of tubulin polymerization
    Diane Macabrey, Alban Longchamp, Michael R. MacArthur, Martine Lambelet, Severine Urfer, Jean-Marc Corpataux, Sebastien Deglise, Florent Allagnat
    bioRxiv 2021.09.09.459573; doi: https://doi.org/10.1101/2021.09.09.459573
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    Sodium Thiosulfate acts as an H2S mimetic to prevent intimal hyperplasia via inhibition of tubulin polymerization
    Diane Macabrey, Alban Longchamp, Michael R. MacArthur, Martine Lambelet, Severine Urfer, Jean-Marc Corpataux, Sebastien Deglise, Florent Allagnat
    bioRxiv 2021.09.09.459573; doi: https://doi.org/10.1101/2021.09.09.459573

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