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

BIANCAMARIA LONGONI^*,1, ELENA BOSCHI^*, GIAN CARLO DEMONTIS, GIAN MICHELE RATTO and FRANCO MOSCA^*

Departments of
^* Oncology, Transplants and Advanced Technologies in Medicine,
Physiology and Biochemistry,
Psychiatry and Neurobiology, University of Pisa, School of Medicine; and
Institute for Neurophysiology, CNR, Pisa, Italy

¹Correspondence: Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Via Paradisa 2, I-56124 Pisa, Italy. E-mail: biancam{at}dfb.unipi.it

Treatment of transplanted patients with cyclosporin A (CSA) may cause adverse effects such as nephrotoxicity and hypertension. As CSA is known to induce oxidative stress in several tissues, it may cause vascular problems by triggering oxidative stress in endothelial cells (EC). However, oxidative stress 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 µM) vs. 8 days clinical (0.5–2.5 µM) doses of CSA on cultured human EC. Pharmacological doses of CSA cause a decrease in cell density 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 and modification of EC morphology, both effects blocked by antioxidants. Therefore, 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 that the oxidative stress induced by clinical concentrations of CSA may be involved in the adverse effects of the drug on the vascular system of transplanted patients via an adaptive response involving Bcl-2 up-regulation rather than an apoptotic process.—Longoni, B., Boschi, E., Demontis, G. C., Ratto, G. M., Mosca, F. Apoptosis and adaptive responses to oxidative stress in human endothelial cells exposed to cyclosporin A correlate with BCL-2 expression levels.

Key Words: confocal microscopy • reactive oxygen species • antioxidants • dihydrorhodamine 123 • melatonin • transplantation

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