Journal Article

CaMKII activation participates in doxorubicin cardiotoxicity and is attenuated by moderate GRP78 overexpression

Tscheschner, Henrike, Schlegel, Philipp, Most, Patrick, Müller, Oliver J., Katus, Hugo A., Raake, Philip W., Meinhardt, Eric, Jungmann, Andreas, Lehmann, Lorenz H.

2019

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Animal models / Animals / Anthracyclines / Apoptosis / Apoptosis - drug effects / Biochemistry / Biocompatibility / Ca2+/calmodulin-dependent protein kinase II / Calcium (reticular) / Calcium - metabolism / Calcium binding proteins / Calcium homeostasis / Calcium ions / Calcium Signaling - drug effects / Calcium signalling / Calcium-binding protein / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism / Calmodulin / Cardiac muscle / Cardiology / Cardiomyocytes / Cardiomyopathy / Cardiotoxicity / Cardiotoxicity - enzymology / Cardiotoxicity - pathology / Cardiotoxicity - physiopathology / Cell death / Cell survival / Chemotherapy / Doxorubicin / Doxorubicin - toxicity / Drug dosages / Endoplasmic reticulum / Enzyme Activation - drug effects / Gene expression / Gene therapy / Genes / Glucose / Heart / Heart cells / Heart failure / Heat-Shock Proteins - metabolism / Homeostasis / Internal medicine / Kinases / Laboratory animals / Leak channels / Male / Medical research / Medicine / Mice, Inbred C57BL / Myocardial diseases / Myocytes, Cardiac - metabolism / Neonates / Newborn infants / p53 Protein / Phospholamban / Phosphorylation / Protein kinases / Proteins / Rats / Risk factors / Sarcoplasmic reticulum / Sarcoplasmic Reticulum - drug effects / Sarcoplasmic Reticulum - metabolism / Survival / Time dependence / Toxicity / Tumor proteins / Tumors / Viruses