PT  - JOURNAL ARTICLE
AU  - Ki Young Kim
AU  - Byeong Gee Kim
AU  - Sun-Ok Kim
AU  - Sung-Eun Yoo
AU  - Yong-Geun Kwak
AU  - Soo-Wan Chae
AU  - Ki Whan Hong
TI  - Prevention of Lipopolysaccharide-Induced Apoptosis by (2<em>S</em>,3<em>S</em>,4<em>R</em>)-<em>N</em>"-Cyano-<em>N</em>-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2<em>H</em>-benzopyran-4-yl)-<em>N</em>′-benzylguanidine, a Benzopyran Analog, in Endothelial Cells
AID  - 10.1124/jpet.300.2.535
DP  - 2002 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 535--542
VI  - 300
IP  - 2
4099  - http://jpet.aspetjournals.org/content/300/2/535.short
4100  - http://jpet.aspetjournals.org/content/300/2/535.full
SO  - J Pharmacol Exp Ther2002 Feb 01; 300
AB  - This study describes the antiapoptotic action of (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine (KR-31378), a novel benzopyran analog, in human umbilical vein endothelial cells (HUVECs) in comparison with its acetylated metabolite, (2S,3S,4R)-N"-cyano-N-(6-acetylamino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine (KR-31612), and with α-tocopherol. Exposure of HUVECs to lipopolysaccharide (LPS) (1 μg/ml) induced time- and concentration-dependent cytotoxicity and oligonucleosomal DNA fragmentation. KR-31378, KR-31612, and α-tocopherol potently suppressed LPS-induced cell death in association with significant reduction in the intracellular reactive oxygen species (ROS) and tumor necrosis factor-α (TNF-α) that are stimulated by LPS. KR-31378 more effectively protected HUVECs from LPS-induced DNA fragmentation and was more effective in peroxyl radical scavenging than α-tocopherol. Incubation with LPS markedly decreased the Bcl-2 level, which was totally reversed by KR-31378 and to a lesser degree by KR-31612 and by α-tocopherol. In contrast, the greatly increased Bax protein and cytochrome c release stimulated by LPS were markedly suppressed by KR-31378 and by KR-31612, and to a lesser degree by α-tocopherol. Taken together, KR-31378 strongly inhibited cell death in HUVECs in association with antiapoptotic effects, which were accompanied by up-regulation of Bcl-2 protein expression and down-regulation of Bax protein and suppression of cytochromec release. KR-31378 also showed the properties to scavenge the intracellular ROS and peroxyl radicals, and to reduce the TNF-α production induced by LPS. The American Society for Pharmacology and Experimental Therapeutics