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Curcumin induces the apoptotic intrinsic pathway via upregulation of reactive oxygen species and JNKs in H9c2 cardiac myoblasts

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Abstract

Curcumin derived from the rhizome of turmeric (Curcuma longa L.), is a well known coloring culinary agent, that has therapeutic properties against diverse pathologies such as cancer, atherosclerosis and heart failure. Given the salutary potential of curcumin, deciphering its mode of action particularly in cardiac cells, is of outstanding value. Accumulating evidence implicates curcumin in the regulation of multiple signaling pathways leading to cell survival or apoptosis. Therefore, the present study aimed at elucidating the molecular mechanisms triggered by curcumin in H9c2 cells. Curcumin was found to activate p38-mitogen-activated protein kinase (p38-MAPK) as well as c-jun NH2 terminal kinases (JNKs), in a dose- and time-dependent manner. We also observed curcumin to impair cell survival by promoting apoptosis, evidenced by chromatin condensation, poly(ADP-ribose) polymerase (PARP) and caspase-3 cleavage, as well as Bax translocation and cytochrome c release into the cytosol. Curcumin-induced apoptosis was ascribed to JNKs, since hindering their activity abolished PARP fragmentation. Furthermore, we identified curcumin to exert a pro-oxidative activity, with 2′,7′-dichlorofluorescin diacetate (DCFH-DA) staining revealing up-regulation of reactive oxygen species (ROS) levels and anti-oxidants found to abrogate PARP cleavage. In conclusion, curcumin was found to stimulate the apoptotic cell death of H9c2 cells by upregulating ROS generation and triggering activation of JNKs. With reports underscoring the capacity of curcumin to perturb the cellular redox balance ensuring survival or enhancing apoptosis, determination of its mode of action appears to be critical. Future studies should assess the appropriate administration conditions of curcumin, so as to optimize its therapeutic potential against cardiovascular pathologies.

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Abbreviations

BSA:

Bovine serum albumin

DMSO:

Dimethyl sulphoxide

DTT:

Ditheiothreitol

ECL:

Enhanced chemiluminescence

ERK:

Extracellular signal-regulated kinase

Hsp:

Heat shock-protein

JNK:

c-Jun NH2 terminal kinase

MAPK:

Mitogen-activated protein kinase

MSK1:

Mitogen and stress activating kinase 1

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PAGE:

Polyacrylamide gel electrophoresis

PARP:

Poly(ADP-ribose) polymerase

PMSF:

Phenyl methyl sulphonyl fluoride

ROS:

Reactive oxygen species

TBS:

Tris-buffered saline

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Acknowledgments

We would like to thank Prof. P. Apostolakos for providing us with the DCFH-DA stain and for his assistance in acquiring the digital images with the Zeiss Axioplan microscope. This work was supported by the Special Research Account of the University of Athens (Project Number: 70/4/11242). The funding body had no involvement in the design of the present study, neither in the experiments performed nor in the analysis of the data or the writing of the report.

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The authors declare that they have no conflict of interest associated with this work.

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  1. Department of Animal and Human Physiology, School of Biology, University of Athens, University Campus, Athens, 157 84, Greece

    Kyriaki Zikaki, Ioanna-Katerina Aggeli, Catherine Gaitanaki & Isidoros Beis

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  1. Kyriaki Zikaki
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Correspondence to Catherine Gaitanaki.

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Zikaki, K., Aggeli, IK., Gaitanaki, C. et al. Curcumin induces the apoptotic intrinsic pathway via upregulation of reactive oxygen species and JNKs in H9c2 cardiac myoblasts. Apoptosis 19, 958–974 (2014). https://doi.org/10.1007/s10495-014-0979-y

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