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.
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-1 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.
Kim
Do-Sung
DS
Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Jeonju, Chonbuk 560-180, South Korea.
Kim
Hyung-Ryong
HR
Woo
Eun-Rhan
ER
Hong
Seong-Tshool
ST
Chae
Han-Jung
HJ
Chae
Soo-Wan
SW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology*; D015342:DNA Probes; D053630:Depsides; D004317:Doxorubicin / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008564:Membrane Potentials; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D000097123:Rosmarinic Acid
D053148:Caspase 3; D020169:Caspases; D002934:Cinnamates; D015342:DNA Probes; D053630:Depsides; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione; D048031:JNK Mitogen-Activated Protein Kinases; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000097123:Rosmarinic Acid; C505410:Casp3 protein, rat