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. H2O2 caused 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 H2O2 exposure 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: Eun-Seok Park, Do-Hyun Kang, Jun Chul Kang, Yong Chang Jang, Min-Ju Lee, Hun-Jong Chung, Kyu Yang Yi, Dae-Eun Kim, Bokyung Kim, Hwa-Sup Shin
• Journal: Archives of pharmacal research (Arch Pharm Res) Vol. 40 Issue 5 Pg. 640-654 (May 2017) ISSN: 1976-3786 [Electronic] Korea (South)
• PMID: 28378219 (Publication Type: Journal Article)

Chemical References

• 2-(methoxycarbonyl(4-methoxyphenyl)methylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide
• Benzimidazoles
• Cardiotonic Agents
• Phenylacetates
• Poly(ADP-ribose) Polymerase Inhibitors
• Reactive Oxygen Species
• Hydrogen Peroxide

Topics

• Animals
• Apoptosis (drug effects)
• Benzimidazoles (chemical synthesis, chemistry, pharmacology)
• Cardiotonic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Survival (drug effects)
• Cells, Cultured
• Heart (drug effects)
• Hydrogen Peroxide
• Oxidative Stress (drug effects)
• Phenylacetates (chemical synthesis, chemistry, pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Rats
• Reactive Oxygen Species (metabolism)