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

• Published in: PloS one Vol. 14; no. 4; p. e0215992
• Main Authors: Tscheschner, Henrike, Meinhardt, Eric, Schlegel, Philipp, Jungmann, Andreas, Lehmann, Lorenz H, Müller, Oliver J, Most, Patrick, Katus, Hugo A, Raake, Philip W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.04.2019; Public Library of Science (PLoS)
• Subjects: 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; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0215992

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.