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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Prevention of Lipopolysaccharide-Induced Apoptosis by (2S,3S,4R)-N"-Cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine, a Benzopyran Analog, in Endothelial Cells

Ki Young Kim, Byeong Gee Kim, Sun-Ok Kim, Sung-Eun Yoo, Yong-Geun Kwak, Soo-Wan Chae and Ki Whan Hong
Journal of Pharmacology and Experimental Therapeutics February 2002, 300 (2) 535-542; DOI: https://doi.org/10.1124/jpet.300.2.535
Ki Young Kim
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Byeong Gee Kim
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Sun-Ok Kim
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Sung-Eun Yoo
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Yong-Geun Kwak
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Soo-Wan Chae
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Ki Whan Hong
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Abstract

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.

Footnotes

  • This study was supported with funding from the Center for Bioactive Substances, Korea Research Institute of Chemical Technology, Daejon, and from the Korea Science and Engineering Foundation, Korea.

  • Abbreviations:
    LPS
    lipopolysaccharide
    TNF-α
    tumor necrosis factor-α
    ROS
    reactive oxygen species
    HUVEC
    human umbilical vein endothelial cell
    MTT
    mitochondrial tetrazolium
    DCFH-DA
    2′,7′-dichlorofluororescine diacetate
    DCFH
    2′,7′-dichlorofluororescine
    PRAC
    peroxyl radical absorbing capacity
    AAPH
    2,2′-azobis(2-amidino-propane) dihydrochloride
    β-PE
    β-phycoerythrin
    • Received August 9, 2001.
    • Accepted November 2, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 2
1 Feb 2002
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Prevention of Lipopolysaccharide-Induced Apoptosis by (2S,3S,4R)-N"-Cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine, a Benzopyran Analog, in Endothelial Cells
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Prevention of Lipopolysaccharide-Induced Apoptosis by (2S,3S,4R)-N"-Cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine, a Benzopyran Analog, in Endothelial Cells

Ki Young Kim, Byeong Gee Kim, Sun-Ok Kim, Sung-Eun Yoo, Yong-Geun Kwak, Soo-Wan Chae and Ki Whan Hong
Journal of Pharmacology and Experimental Therapeutics February 1, 2002, 300 (2) 535-542; DOI: https://doi.org/10.1124/jpet.300.2.535

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Prevention of Lipopolysaccharide-Induced Apoptosis by (2S,3S,4R)-N"-Cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine, a Benzopyran Analog, in Endothelial Cells

Ki Young Kim, Byeong Gee Kim, Sun-Ok Kim, Sung-Eun Yoo, Yong-Geun Kwak, Soo-Wan Chae and Ki Whan Hong
Journal of Pharmacology and Experimental Therapeutics February 1, 2002, 300 (2) 535-542; DOI: https://doi.org/10.1124/jpet.300.2.535
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