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Vol. 300, Issue 2, 709-715, February 2002

Inhibition of Lipopolysaccharide-Induced Apoptosis by Cilostazol in Human Umbilical Vein Endothelial Cells

Ki Young Kim, Hwa Kyoung Shin, Jae Moon Choi and Ki Whan Hong

Department of Pharmacology, College of Medicine, and Research Institute of Genetic Engineering, Pusan National University, Pusan, Korea

This work describes the pharmacological inhibition by cilostazol and its metabolites, OPC-13015 and OPC-13213, of the apoptosis in the human umbilical vein endothelial cells (HUVECs) damaged by lipopolysaccharide (LPS) in comparison with its analog, cilostamide. Cilostazol and OPC-31213 caused a significant suppression of cell death induced by LPS (1 µg/ml) in a concentration-dependent manner but a modest suppression by cilostamide and OPC-13015. These compounds potently inhibited the 5,5-dimethyl-1-pyrroline-1-oxide (DMPO)/·OH adduct formation and significantly reduced the increased intracellular reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha ) production induced by LPS (1 µg/ml). An apoptotic death of HUVECs by 1 µg/ml LPS (DNA ladders on electrophoresis) was strongly suppressed by all these compounds. Incubation with LPS caused a marked decrease in Bcl-2 protein, which was significantly reversed by cilostazol and its analogs. The greatly increased Bax protein expression and cytochrome c release by LPS were, in contrast, suppressed by cilostazol and, to a lesser degree, by others. In conclusion, cilostazol and its analogs exert a strong protection against apoptotic cell death by scavenging hydroxyl radicals and intracellular ROS with reduction in TNF-alpha formation and by increasing Bcl-2 protein expression and decreasing Bax protein and cytochrome c release.

0022-3565/02/3002-0709$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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