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Abstract
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.
Highlights
The anthracycline doxorubicin (Dox) is an effective and frequently applied anticancer treatment
As our aim was to investigate the potential of prophylactic Glucose regulated protein 78 (GRP78) overexpression, we were first interested in changes of endogenous GRP78 expression in Dox treated neonatal rat ventricular cardiomyocytes (NRVCM)
GRP78 protects from doxorubicin cardiotoxicity dose and time dependent downregulation of GRP78 could be observed, with first changes in GRP78 levels occurring after 16h (Fig 1A and 1B)
Summary
The anthracycline doxorubicin (Dox) is an effective and frequently applied anticancer treatment. Dox treatment comes with severe adverse effects substantially limiting its use as chemotherapeutic. The risk of developing cardiomyopathy increases with the cumulative dose [1]. Molecular mechanisms are still controversial and therapeutic options are still limited and mainly restricted to symptomatic approaches.
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