CaMKII activation participates in doxorubicin cardiotoxicity and is attenuated by moderate GRP78 overexpression
The clinical use of the chemotherapeutic doxorubicin (Dox) is limited by cardiotoxic side-effects. One of the early Dox effects is induction of a sarcoplasmic reticulum (SR) Ca2+ leak. The chaperone Glucose regulated protein 78 (GRP78) is important for Ca2+ homeostasis in the endoplasmic reticulum (...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
April 29, 2019
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| In: |
PLOS ONE
Year: 2019, Volume: 14, Issue: 4, Pages: 1-20 |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0215992 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1371/journal.pone.0215992 Verlag, kostenfrei, Volltext: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215992 
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| Author Notes: | Henrike Tscheschner, Eric Meinhardt, Philipp Schlegel, Andreas Jungmann, Lorenz H. Lehmann, Oliver J. Müller, Patrick Most, Hugo A. Katus, Philip W. Raake |
| Summary: | The clinical use of the chemotherapeutic doxorubicin (Dox) is limited by cardiotoxic side-effects. One of the early Dox effects is induction of a sarcoplasmic reticulum (SR) Ca2+ leak. The chaperone Glucose regulated protein 78 (GRP78) is important for Ca2+ homeostasis in the endoplasmic reticulum (ER)—the organelle corresponding to the SR in non-cardiomyocytes—and has been shown to convey resistance to Dox in certain tumors. Our aim was to investigate the effect of cardiac GRP78 gene transfer on Ca2+ dependent signaling, cell death, cardiac function and survival in clinically relevant in vitro and in vivo models for Dox cardiotoxicity.By using neonatal cardiomyocytes we could demonstrate that Dox induced Ca2+ dependent Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activation is one of the factors involved in Dox cardiotoxicity by promoting apoptosis. Furthermore, we found that adeno-associated virus (AAV) mediated GRP78 overexpression partly protects neonatal cardiomyocytes from Dox induced cell death by modulating Ca2+ dependent pathways like the activation of CaMKII, phospholamban (PLN) and p53 accumulation. Most importantly, cardiac GRP78 gene therapy in mice treated with Dox revealed improved diastolic function (dP/dtmin) and survival after Dox treatment. In conclusion, our results demonstrate for the first time that Ca2+ dependent CaMKII activation fosters Dox cardiomyopathy and provide additional insight into possible mechanisms by which GRP78 overexpression protects cardiomyocytes from Doxorubicin toxicity. |
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| Item Description: | Gesehen am 27.05.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0215992 |