Na+/Ca(2+ )Exchanger a Druggable Target to Promote beta -Cell Proliferation and Function

Détails

Ressource 1Télécharger: js.2017-00370.pdf (1071.38 [Ko])
Etat: Serval
Version: Final published version
ID Serval
serval:BIB_464F9423B131
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Na+/Ca(2+ )Exchanger a Druggable Target to Promote beta -Cell Proliferation and Function
Périodique
Journal of the Endocrine Society
Auteur(s)
Papin J., Zummo F.P., Pachera N., Guay C., Regazzi R., Cardozo A.K., Herchuelz A.
ISSN
2472-1972 (Electronic)
ISSN-L
2472-1972
Statut éditorial
Publié
Date de publication
2018
Peer-reviewed
Oui
Volume
2
Numéro
7
Pages
631-645
Langue
anglais
Résumé
An important feature of type 2 diabetes is a decrease in <i>β</i> -cell mass. Therefore, it is essential to find new approaches to stimulate <i>β</i> -cell proliferation. We have previously shown that heterozygous inactivation of the Na <sup>+</sup> /Ca <sup>2+</sup> exchanger (isoform 1; NCX1), a protein responsible for Ca <sup>2+</sup> extrusion from cells, increases <i>β</i> -cell proliferation, mass, and function in mice. Here, we show that <i>Ncx</i> 1 inactivation also increases <i>β</i> -cell proliferation in 2-year-old mice and that NCX1 inhibition in adult mice by four small molecules of the benzoxyphenyl family stimulates <i>β</i> -cell proliferation both <i>in vitro</i> and <i>in vivo</i> . NCX1 inhibition by small interfering RNA or small molecules activates the calcineurin/nuclear factor of activated T cells (NFAT) pathway and inhibits apoptosis induced by the immunosuppressors cyclosporine A (CsA) and tacrolimus in insulin-producing cell. Moreover, NCX1 inhibition increases the expression of <i>β</i> -cell-specific genes, such as <i>Ins1, Ins2,</i> and <i>Pdx</i> 1, and inactivates/downregulates the tumor suppressors retinoblastoma protein (pRb) and miR-193a and the cell cycle inhibitor p53. Our data show that Na <sup>+</sup> /Ca <sup>2+</sup> exchange is a druggable target to stimulate <i>β</i> -cell function and proliferation. Specific <i>β</i> -cell inhibition of Na <sup>+</sup> /Ca <sup>2+</sup> exchange by phenoxybenzamyl derivatives may represent an innovative approach to promote <i>β</i> -cell regeneration in diabetes and improve the efficiency of pancreatic islet transplantation for the treatment of the disease.
Mots-clé
Na/Ca exchange, calcineurein/NFAT pathway, diabetes, β-cell
Pubmed
Web of science
Open Access
Oui
Création de la notice
15/08/2018 8:12
Dernière modification de la notice
08/05/2019 17:56
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