Upregulation of miR-200c-3p induced by NaF promotes endothelial apoptosis by activating Fas pathway.

Fluoride has been considered as a risk factor of cardiovascular disease due to its endothelial toxicology. However, the mechanism underlying the endothelial toxicity of fluoride has not been clearly illustrated. MiR-200c-3p was strongly linked with endothelial function and its level is increased in serum of fluorosis patients, but it is unclear the role of miR-200c-3p in the fluoride induced endothelial dysfunction. In this study, we confirmed that fluoride exposure induced the apoptosis of endothelial cells both in established rats model and cultured human umbilical vein endothelial cells (HUVECs). And miR-200c-3p was found to be upregulated in NaF treated HUVECs. Fluoride stimulation increased caspase-dependent apoptosis through miR-200c-3p upregulation, with repressing expression of its target gene Fas-associated phosphatase 1 (Fap-1), which functioned as Fas inhibitor. This resulted in activation of Fas-associated extrinsic apoptosis via interaction with increased Fas, Fadd, Cleaved Caspase-8 and Cleaved Caspase-3. The activation of Fas-associated extrinsic apoptosis was abrogated by miR-200c-3p inhibitor. Furthermore, the antiapoptotic effect of downregulated miR-200c-3p was restored by Fap-1 siRNA. These results suggested a determinant role of the miR-200c-3p/Fap-1 axis in fluoride induced endothelial apoptosis.