5-AIQ inhibits H2O2-induced apoptosis through reactive oxygen species scavenging and Akt/GSK-3β signaling pathway in H9c2 cardiomyocytes.

Abstract

Poly(adenosine 5'-diphosphate ribose) polymerase (PARP) is a nuclear enzyme activated by DNA strand breaks and plays an important role in the tissue injury associated with ischemia and reperfusion. The aim of the present study was to investigate the protective effect of 5-aminoisoquinolinone (5-AIQ), a PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cardiomyocytes. 5-AIQ pretreatment significantly protected against H2O2-induced cell death, as determined by the XTT assay, cell counting, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and Western blot analysis of apoptosis-related proteins such as caspase-3, Bax, and Bcl-2. Upregulation of antioxidant enzymes such as manganese superoxide dismutase and catalase accompanied the protective effect of 5-AIQ on H2O2-induced cell death. Our data also showed that 5-AIQ pretreatment protected H9c2 cells from H2O2-induced apoptosis by triggering activation of Akt and glycogen synthase kinase-3β (GSK-3β), and that the protective effect of 5-AIQ was diminished by the PI3K inhibitor LY294002 at a concentration that effectively abolished 5-AIQ-induced Akt and GSK-3β activation. In addition, inhibiting the Akt/GSK-3β pathway by LY294002 significantly attenuated the 5-AIQ-mediated decrease in cleaved caspase-3 and Bax activation and H9c2 cell apoptosis induction. Taken together, these results demonstrate that 5-AIQ prevents H2O2-induced apoptosis in H9c2 cells by reducing intracellular reactive oxygen species production, regulating apoptosis-related proteins, and activating the Akt/GSK-3β pathway.

• Authors: Eun-Seok Park, Jun Chul Kang, Do-Hyun Kang, Yong Chang Jang, Kyu Yang Yi, Hun-Jong Chung, Jong Seok Park, Bokyung Kim, Zhong-Ping Feng, Hwa-Sup Shin
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 268 Issue 1 Pg. 90-8 (Apr 01 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 23352507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• 5-aminoisoquinolinone
• Isoquinolines
• Poly(ADP-ribose) Polymerase Inhibitors
• Reactive Oxygen Species
• Hydrogen Peroxide
• Poly(ADP-ribose) Polymerases
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line
• Cell Survival (drug effects, physiology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Hydrogen Peroxide (antagonists & inhibitors, pharmacology)
• In Situ Nick-End Labeling
• Isoquinolines (pharmacology)
• Myocytes, Cardiac (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)