RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 535
OP 542
DO 10.1124/jpet.300.2.535
VO 300
IS 2
A1 Ki Young Kim
A1 Byeong Gee Kim
A1 Sun-Ok Kim
A1 Sung-Eun Yoo
A1 Yong-Geun Kwak
A1 Soo-Wan Chae
A1 Ki Whan Hong
YR 2002
UL http://jpet.aspetjournals.org/content/300/2/535.abstract
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