Apoptosis and adaptive responses to oxidative stress in human endothelial cells exposed to cyclosporin A correlate with BCL-2 expression levels

Treatment of transplanted patients with cyclosporin A (CSA) may cause adver se effects such as nephrotoxicity and hypertension, As CSA is kn1own to ind uce oxidative stress in several tissues, it may cause vascular problems by triggering oxidative stress in endothelial cells (EC), However, oxidative s tress has been reported for acute exposure to CSA concentrations exceeding its clinical range, whereas immunosuppression requires life-long treatment with therapeutic concentrations. We therefore compared the effects of 21 h pharmacological (200 muM) vs. 8 days clinical (0.5-2.5 muM) doses of CSA on cultured human EC. Pharmacological doses of CSA cause a decrease in cell d ensity via apoptosis and a down-regulation of the antiapoptotic protein Bcl -2. However, these effects are independent of CSA-induced oxidative stress. In contrast, therapeutic concentrations of CSA cause Bcl-2 up-regulation a nd modification of EC morphology, both effects blocked by antioxidants, The refore, a low level of oxidants may act in EC as second messengers that up- regulate Bcl-2, thus promoting survival of impaired EC, Our data suggest th at the oxidative stress induced by clinical concentrations of CSA may be in volved in the adverse effects of the drug on the vascular system of transpl anted patients via an adaptive response involving Bcl-2 up-regulation rathe r than an apoptotic process.-Longoni, B., Boschi, E., Demontis, G. C., Ratt o, C. M., Mosca, F. Apoptosis and adaptive responses to oxidative stress in human endothelial cells exposed to cyclosporin A correlate with BCL-2 expr ession levels.