57 - Séance principale
Oncology and metabolism
3 juin 2021, 17:35 - 19:05, Stream 4: Video Invited, SST, SSCViscérale & ARS
Video: Sodium thiosulfate prevents intimal hyperplasia via inhibition of tubulin polymerization and smooth muscle cell proliferation
D. Macabrey, M. Lambelet, A. Longchamp, J.-M. Corpataux, F. Allagnat, S. Déglise, Presenter: D. Macabrey (Lausanne)
Bypass surgeries and other endovascular approaches to treat arterial occlusive diseases suffer from limited long-term patency due to re-occlusive vascular adaptations, a process called intimal hyperplasia (IH). IH develops in response to vessel injury, loss of endothelial cells (EC), leading to inflammation, dedifferentiation and proliferation of vascular smooth muscle cells (VSMC). Hydrogen Sulfide (H2S) is an endogenously produced gas, with anti-oxidant and anti-inflammatory properties. The H2S salt sodium hydrogen sulfide (NaHS) reduces IH in rodent models. Here, we tested the therapeutic potential against IH of the clinically approved thiol source sodium thiosulfate (STS) in human vein segments obtained from vascular patients and in a mouse model of IH.
Human veins segments obtained from patients undergoing lower bypass surgery maintained in culture ex-vivo for 7 days to stimulate IH were treated with NaHS or STS. Mouse subjected to carotid artery stenosis to stimulate IH were treated systemically with NaHS or STS. IH was measured by histomorphology and VSMC proliferation measure by proliferating cell nuclear antigen (PCNA). In addition, primary human vascular smooth muscle cells (VSMC) were exposed in-vitro to the same H2S donors. Migration and proliferation of these primary cells were measured using a wound healing assay and BrDU incorporation, respectively. To assess cytoskeletal organization, tubulin and actin fluorescent stainings were performed on VSMC.
STS and NaHS similarly prevented the development of IH in human vein segments ex-vivo and in carotids in vivo. PCNA staining of human veins or mouse arteries suggest that the H2S donors reduce IH by inhibiting VSMC proliferation. In vitro, STS and NaHS similarly inhibited migration and proliferation of primary VSMC. Both STS and NaHS stimulated protein persulfidation and circulating sulfane sulfur levels. Immunofluorescent stainings of cytoskeletal proteins revealed that STS and NaHS destabilized microtubules organization probably via persulfidation of the tubulin protein.
Currently, there is limited strategy to reduce IH. STS represents a clinically approved relevant source of H2S, which holds great promise as a new therapeutic agent to limit VSMC proliferation in the context of IH.