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

• Published in: The FASEB journal Vol. 15; no. 3; pp. 731 - 740
• Main Authors: LONGONI, BIANCAMARIA, BOSCHI, ELENA, DEMONTIS, GIAN CARLO, RATTO, GIAN MICHELE, MOSCA, FRANCO
• Format: Journal Article
• Language: English
• Published: United States Federation of American Societies for Experimental Biology 01-03-2001
• Subjects: an¬tioxidants; Apoptosis - genetics; Apoptosis - physiology; Benzopyrans; Cell Division - drug effects; Cell Size - drug effects; Cells, Cultured; confocal microscopy; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclosporine - adverse effects; Cyclosporine - pharmacology; dihydrorhodamine 123; DNA Fragmentation; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Fluorescent Dyes - metabolism; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacology; melatonin; Microscopy, Confocal; Oxidative Stress - physiology; reactive oxygen species; Reactive Oxygen Species - metabolism; Rhodamine 123 - metabolism; transplan¬tation
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.00-0163com

ABSTRACT
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 concentra¬tions 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 con¬trast, 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 im¬paired 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 expres¬sion levels. FASEB J. 15, 731‐740 (2001)