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

• Verfasst von: Tscheschner, Henrike [VerfasserIn]
• Verfasst von: Meinhardt, Eric [VerfasserIn]
• Verfasst von: Schlegel, Philipp [VerfasserIn]
• Verfasst von: Jungmann, Andreas [VerfasserIn]
• Verfasst von: Lehmann, Lorenz [VerfasserIn]
• Verfasst von: Müller, Oliver J. [VerfasserIn]
• Verfasst von: Most, Patrick [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Raake, Philip [VerfasserIn]
• Titel: CaMKII activation participates in doxorubicin cardiotoxicity and is attenuated by moderate GRP78 overexpression
• Verf.angabe: Henrike Tscheschner, Eric Meinhardt, Philipp Schlegel, Andreas Jungmann, Lorenz H. Lehmann, Oliver J. Müller, Patrick Most, Hugo A. Katus, Philip W. Raake
• E-Jahr: 2019
• Jahr: April 29, 2019
• Umfang: 20 S.
• Fussnoten: Gesehen am 27.05.2019
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2019
• Band/Heft Quelle: 14(2019), 4, Artikel-ID e0215992, Seite 1-20
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0215992
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Apoptosis
• Sach-SW: Cancer treatment
• Sach-SW: Cardiomyocytes
• Sach-SW: Cardiovascular physiology
• Sach-SW: Hyperexpression techniques
• Sach-SW: Immunoblotting
• Sach-SW: Luciferase
• Sach-SW: Phosphorylation
• K10plus-PPN: 1666356255
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

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.