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1 Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Denver, Colorado, United States
* To whom correspondence should be addressed. E-mail: charles.edelstein{at}uchsc.edu.
The role of caspases and calpain in cisplatin-induced endothelial cell death is unknown. Thus, we investigated whether caspases and calpain are mediators of cisplatin-induced apoptosis and necrosis in endothelial cells. Cultured pancreatic microvascular endothelial (MS1) cells were exposed to 10 and 50 µM cisplatin. Apoptosis or necrosis was determined by Hoechst 33342 and propidium iodide (PI) nuclear staining. Cells treated with 10 µM of cisplatin had normal ATP levels, increased caspase-3-like activity, excluded PI and demonstrated morphological characteristics of apoptosis at 24 hours. Cells treated with 50 µM cisplatin had severe ATP depletion, increased caspase-3-like activity and displayed extensive PI staining indicative of necrosis at 24 hours. There was a dose-dependent increase in caspase-2-like activity and Smac/DIABLO protein. Calpain activity increased significantly with 50 µM, but not 10 µM cisplatin at 24 hours. With 50 µM cisplatin, ATP levels were significantly reduced starting at 18 hours, caspase-2- and caspase-3-like activities were significantly increased starting at 18 hours, LDH release started at 8 hours with maximum increase at 18-24 hours. Calpain activity was not increased before 24 hours. The increase in LDH release and the nuclear PI staining with 50 µM cisplatin at 24 hours was reduced by either the pancaspase inhibitor, Q-VD-OPH or the calpain inhibitor, PD150606. Calpain inhibitor had no effect on caspase-3-like activity. In conclusion, in cisplatin-treated endothelial cells, caspases, the major mediators of apoptosis, can also cause necrosis. A calpain inhibitor protects against necrosis without affecting caspase-3-like activity suggesting that calpain mediated necrosis is independent of caspase-3.
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