Open AccessCaMKII activation participates in doxorubicin cardiotoxicity and is attenuated by moderate GRP78 overexpression
Author(s) -
Henrike Tscheschner,
Eric Meinhardt,
Philipp Schlegel,
Andreas Jungmann,
Lorenz Lehmann,
Oliver Müller,
Patrick Most,
Hugo A. Katus
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0215992
Subject(s) - cardiotoxicity , phospholamban , doxorubicin , endoplasmic reticulum , microbiology and biotechnology , programmed cell death , calmodulin , pharmacology , cancer research , apoptosis , cardiac function curve , homeostasis , heart failure , chemistry , biology , medicine , toxicity , biochemistry , chemotherapy , calcium
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) Ca 2+ leak. The chaperone Glucose regulated protein 78 (GRP78) is important for Ca 2+ 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 Ca 2+ 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 Ca 2+ dependent Ca 2+ /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 Ca 2+ 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 Ca 2+ dependent CaMKII activation fosters Dox cardiomyopathy and provide additional insight into possible mechanisms by which GRP78 overexpression protects cardiomyocytes from Doxorubicin toxicity.