title: Protective effect of KR-31378 on oxidative stress in cardiac myocytes.
abstract: In this study, we investigated whether a novel anti-ischemic KATP opener KR-31378 [(2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methly-2-dimethoxymethly-2H-benzopyran-4-yl)-N'-benzylguanidine] has protective effect against oxidative stress-induced death in heart-derived H9c2 cells. Cell death was induced by BSO, butionine sulfoximine, which inhibits GSH synthesis and subsequently increases reactive oxygen species (ROS) level. Cell death was quantitatively determined by measuring lactate dehydrogenase (LDH) activity and stained by Hoechst 33258. BSO-induced ROS production and mitochondrial membrane potential (MMP) were measured using 2',7'-dichlorofluorescein diacetate oxidation and rhodamine 123, respectively. Both the LDH release and the ROS elevation induced by treatment of H9c2 cells with 10 mM BSO, were significantly decreased by KR-31378. These protective effect and antioxidant effect of KR-31378 appeared to be independent on KATP channel opening. Cells exposed to BSO showed an early reduction in MMP, and this reduction in MMP was significantly reversed by treatment with KR-31378. Caspase-3 activity in BSO treated H9c2 cells was remarkably increased, and this increased caspase-3 activity was significantly reversed by KR-31378. In conclusion, our results suggest that KR-31378 can produce cardioprotective effect against oxidative stress-induced cell death through antioxidant mechanism.
authors.affiliation: Department of Physiology, School of Medicine, Ajou University, Suwon, Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Dong-Ha
authors.initials: DH
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Lim
authors.forename: Ho Soon
authors.initials: HS
authors.lastname: Kim
authors.forename: Soo Hwan
authors.initials: SH
authors.lastname: Lee
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Baik
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Moon
authors.forename: Yi-Sook
authors.initials: YS
authors.lastname: Jung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry; D019328:Buthionine Sulfoximine / Q000037:antagonists & inhibitors / Q000633:toxicity; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000737:chemistry; D006146:Guanidines / Q000494:pharmacology*; D006880:Hydroxy Acids / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008856:Microscopy, Fluorescence; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011714:Pyrans / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001562:Benzimidazoles; D061945:Caspase Inhibitors; D003652:Decanoic Acids; D005452:Fluoresceins; D006146:Guanidines; D006880:Hydroxy Acids; C438686:N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; D026902:Potassium Channel Blockers; D011714:Pyrans; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C447680:hoechst 32258; D019328:Buthionine Sulfoximine; C037631:2',7'-dichlorofluorescein; C052853:5-hydroxydecanoic acid; C114623:clamikalant; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D020169:Caspases; D013890:Thiourea