Inhibitory effects of rosmarinic acid on adriamycin-induced apoptosis in H9c2 cardiac muscle cells by inhibiting reactive oxygen species and the activations of c-Jun N-terminal kinase and extracellular signal-regulated kinase

被引:122
作者
Kim, DS
Kim, HR
Woo, ER
Hong, ST
Chae, HJ [1 ]
Chae, SW
机构
[1] Chonbuk Natl Univ, Sch Med, Dept Pharmacol, Jeonju 560180, South Korea
[2] Chonbuk Natl Univ, Sch Med, Cardiovasc Res Inst, Jeonju 560180, South Korea
[3] Sch Dent, Dept Dent Pharmacol, Iksan, South Korea
[4] Sch Dent, Nano Sci & Technol Res Inst, Iksan, South Korea
[5] Chosun Univ, Coll Pharm, Kwangju, South Korea
[6] Chosun Univ, Res Ctr Proteineous Mat, Kwangju, South Korea
[7] Chonbuk Natl Univ, Sch Med, Dept Microbiol, Jeonju, South Korea
关键词
rosmarinic acid; ROS; adriamycin; JNK; ERK; AP-1; apoptosis;
D O I
10.1016/j.bcp.2005.06.026
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Rosmarinic acid (RA) is a naturally occurring polyphenolic and is found in several herbs in the Lamiaceae family, such as, Perilla frutescens. ADR is a potent anti-tumor drug, but is unfortunately potently cardiotoxic. This study was undertaken to investigate the inhibitory effect of RA on ADR-induced apoptosis in H9c2 cardiac muscle cells at a mechanistic level. In vitro, ADR significantly decreased the viabilities of H9c2 cells, and this was accompanied by apoptotic features, such as a change in nuclear morphology and caspase protease activation. RA was found to markedly inhibit these apoptotic characteristics by reducing intracellular ROS generation and by recovering the mitochondria membrane potential (Delta psi). In addition, RA reversed the downregulations of GSH, SOD and Bcl-2 by ADR. In the present study, ADR was found to activate c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), transcriptional factor-activator-protein (AP)- 1. We found that c-fos, Jun-B, Jun-D and p-c-Jun were super shifted by ADR, indicating that these proteins have an important role in the ADR-induced AP- I activation. The inhibitions of JNK and ERK using appropriate inhibitors or dominant negative cell lines reduced ADR-induced apoptosis in H9c2 cardiac muscle cells. Taken together, these results suggest that RA can inhibit ADR-induced apoptosis in H9C2 cardiac muscle cells by inhibiting ROS generation and JNK and ERK activation. Thus, we propose that RA should be viewed as a potential chemotherapeutic. that inhibits cardiotoxicity in ADR-exposed patients. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:1066 / 1078
页数:13
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