title: Cardioprotective effect of KR-33889, a novel PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cells and isolated rat hearts.
abstract: Oxidative stress plays a critical role in cardiac injury during ischemia/reperfusion (I/R). Despite a potent cardioprotective activity of KR-33889, a novel poly (ADP-ribose) polymerase inhibitor, its underlying mechanism remains unresolved. This study was designed to investigate the protective effects of KR-33889 against oxidative stress-induced apoptosis in rat cardiomyocytes H9c2 cells and isolated rat hearts. H2O2caused severe injury to H9c2 cells, mainly due to apoptosis, as revealed by TUNEL assay. However, KR-33889 pretreatment significantly attenuated H2O2-induced apoptosis of H9c2 cells, which was accompanied by decrease in expression of both cleaved caspase-3 and Bax and increase in Bcl-2 expression and the ratio of Bcl-2/Bax. KR-33889 also significantly enhanced the expression of anti-oxidant enzymes including heme oxygenase-1, Cu/Zn-superoxide dismutase (SOD), Mn-SOD, and catalase, thereby inhibiting production of intracellular ROS. Furthermore, KR-33889 reversed H2O2-induced decrease in phosphorylation of Akt, GSK-3β, ERK1/2, p38 MAPK, and SAPK/JNK during most H2O2exposure time. In globally ischemic rat hearts, KR-33889 inhibited both I/R-induced decrease in cardiac contractility and apoptosis by increasing Bcl-2, decreasing both cleaved caspase-3 and Bax expression, and enhancing expression of anti-oxidant enzymes. Taken together, these results suggest that KR-33889 may have therapeutic potential to prevent I/R-induced heart injury in ischemic heart diseases mainly by reducing oxidative stress-mediated myocardial apoptosis.
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Sciences, Konkuk University, Chungju, 27478, Korea.|Department of Biomedical Laboratory Science, Kyungbok University, Pochen, 11138, Korea.
authors.forename: Eun-Seok
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Sciences, Konkuk University, Chungju, 27478, Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Kang
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Sciences, Konkuk University, Chungju, 27478, Korea.
authors.forename: Jun Chul
authors.initials: JC
authors.lastname: Kang
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Sciences, Konkuk University, Chungju, 27478, Korea.
authors.forename: Yong Chang
authors.initials: YC
authors.lastname: Jang
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Sciences, Konkuk University, Chungju, 27478, Korea.
authors.forename: Min-Ju
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Industrial Medicine Department, Chungju Hospital, Konkuk Medical School, Konkuk University, Chungju, 27478, Korea.
authors.forename: Hun-Jong
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Daejeon, Chungnam, 34114, Korea.
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.affiliation: Department of Biomedical Laboratory Science, Kyungbok University, Pochen, 11138, Korea.
authors.forename: Dae-Eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: Department of Physiology, Konkuk Medical School, Konkuk University, Chungju, 27478, Korea.
authors.forename: Bokyung
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Sciences, Konkuk University, Chungju, 27478, Korea. hsshin@kku.ac.kr.
authors.forename: Hwa-Sup
authors.initials: HS
authors.lastname: Shin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects*; D006861:Hydrogen Peroxide; D018384:Oxidative Stress / Q000187:drug effects*; D010648:Phenylacetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C534784:2-(methoxycarbonyl(4-methoxyphenyl)methylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide; D001562:Benzimidazoles; D002316:Cardiotonic Agents; D010648:Phenylacetates; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide
keywords: Apoptosis; Ischemia/reperfusion; KR-33889; Oxidative stress; PARP inhibitor