Inhibition of the TRPM4 cation channel prevents human aortic valve interstitial cells radiation-induced remodeling - 21/05/25
, Benoit D. Roussel 2, Corentin Kerevel 1, Arthur Boileve 1, Maysan Touhiar 1, Alexandre Lebrun 1, Vladimir Saplacan 3, Alain Manrique 1, Christophe Simard 1, Romain Guinamard 1
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Résumé |
Introduction |
Thoracic radiotherapy can induce aortic stenosis, several decades later, but mechanisms leading to this radiation-induced aortic valve remodeling are not well known. In vivo, we showed that the TRPM4 cation channel participates in aortic valve remodeling induced by X radiation in mice. Moreover, in an in vitro model, we also showed that TRPM4 participates in the remodeling of human interstitials cells from aortic valves (hVIC). Therefore, we hypothesized that the effect of X radiation on valve remodeling could involve TRPM4 in those cells.
Objective |
Our project aims to determine whether TRPM4 channel is involved in the radiation-induced remodeling of hVIC.
Method |
Human VIC were isolated by enzymatic digestion from aortic valves obtained during surgical aortic valve replacement. Cells were divided into 4 culture groups: standard media (SM), pro-calcifying media (PM), PM+9-phenanthrol (a TRPM4 inhibitor) or PM+shRNA-TRPM4. hVIC were irradiated with a Faxitron X irradiator at 8Gy. 10 days post-irradiation, surface, viability, cell cycle and proliferation were measured. Cell senescence was also evaluated by quantification of β-galactosidase activity. Osteogenic markers (BMP2, Runx2, ALP) and TRPM4 mRNA expression were quantified by qPCR.
Results |
Cell irradiation induced an increase of hVIC surface and a diminution of their proliferation. PM conditions amplified these effects, which were reduced when the cells were cultured in presence of 9-phenanthrol or shRNA-TRPM4. No variation of viability was detected. Irradiation induced an increase of the proportion of cells in G0, an effect amplified by PM that was reduced by 9-phenanthrol or shRNA-TRPM4. An increase of cell senescence was observed 10 days after irradiation, which was amplified by PM. This senescence was reduced in presence of TRPM4 inhibitor or shRNA-TRPM4. Irradiation of hVIC induced an increase of TRPM4, BMP2, Runx2 and ALP mRNA expression which were reduced by inhibition or repression of TRPM4.
Conclusion |
TRPM4 is involved in hVIC remodeling induced by irradiation by promoting cell senescence and osteogenic transition. TRPM4 may thus be evaluated as a therapeutic target to diminish valvular effects of radiotherapy.
This project was supported by GIP Cancéropôle Nord-Ouest and ANR-24-CE14-1977-01.
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Vol 118 - N° 6-7S1
P. S211 - juin 2025 Retour au numéro
Article précédent
- Functional characterization of a TRPM4 cation channel on human aortic valve endothelial cells
- Corentin Kerevel, Margaux Aize, Alexandre Lebrun, Vladimir Saplacan, Alain Manrique, Romain Guinamard, Christophe Simard
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