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KMID : 0043320170400050640
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Archives of Pharmacal Research
2017 Volume.40 No. 5 p.640 ~ p.654
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Cardioprotective effect of KR-33889, a novel PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cells and isolated rat hearts
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Park Eun-Seok
Kang Do-Hyun
Kang Jun-Chul
Jang Yong-Chang
Lee Min-Ju
Chung Hun-Jong
Yi Kyu-Yang
Kim Dae-Eun
Kim Bo-Kyung
Shin Hwa-Sup
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Abstract
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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.
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KEYWORD
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KR-33889, PARP inhibitor, Apoptosis, Ischemia/reperfusion, Oxidative stress
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