RESUMEN
Although mesenchymal stem cells (MSCs) are being tested for cardiac repair, the majority of transplanted cells undergo apoptosis in the ischaemic heart because of the effects of ischaemia/reperfusion, poor blood supply and other pro-apoptotic factors. Several experimental and clinical studies have suggested that cyclosporin A (CsA) treatment reduces apoptosis in human endothelial cells and neurocytes. However, the effect of CsA on the apoptosis in MSCs is still unclear. In this study, we investigated whether CsA could inhibit hypoxia/ reoxygenation (H/R)-induced apoptosis in MSCs. MSCs pre-incubated with or without CsA were subjected to 6 h of hypoxia followed by 12 h of reoxygenation. Our data showed that pre-incubation with 0.5-5 microM CsA dose-dependently protected the MSCs from H/R injury, as evidenced by decreased apoptosis and increased cell viability. CsA inhibited the H/R-induced translocation of cytochrome c, increased bcl-2 expression and restored mitochondrial membrane potential. CsA also increased the expression of p-BAD. We propose that preincubation MSCs with CsA inhibits MSC apoptosis through the mitochondrial and BAD pathway.
Asunto(s)
Apoptosis/efectos de los fármacos , Ciclosporina/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Daño por Reperfusión/patología , Animales , Supervivencia Celular/efectos de los fármacos , Citocromos c/metabolismo , Activación Enzimática/efectos de los fármacos , Hipoxia/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Factores de Transcripción NFATC/metabolismo , Transporte de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2 , Ratas , Ratas Sprague-Dawley , Proteína X Asociada a bcl-2/biosíntesis , Proteína Letal Asociada a bcl/metabolismoRESUMEN
New series of catechol ether type derivatives 5, 6 have been synthesized and applied to biological tests. Even though it is a preliminary data, some of our target molecules show the promising result against PDE IV inhibition. SAR and biological studies with synthetic compounds will be discussed in detail.