Ionizing radiation regulates cardiac Ca handling via increased ROS and activated CaMKII

Can M. Sag, Hendrik A. Wolff, Kay Neumann, Marie-Kristin Opiela, Juqian Zhang, Felicia Steuer, Thomas Sowa, Shamindra Gupta, Markus Schirmer, Mark Huenlich, Margret Rave-Fraenk, Clemens F. Hess, Mark E. Anderson, Ajay M. Shah, Hans Christiansen, Lars S. Maier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after similar to 1 h) as well as chronically (after similar to 1 week). IR induced a dose-dependent effect on myocytes' systolic function with acutely increased, but chronically decreased Ca transient amplitudes, which was associated with an acutely unaltered but chronically decreased sarcoplasmic reticulum (SR) Ca load. Likewise, in vivo echocardiography of anaesthetized mice revealed acutely enhanced left ventricular contractility (strain analysis) that declined after 1 week. Irradiated myocytes showed persistently increased diastolic SR Ca leakage, which was acutely compensated by an increase in SR Ca reuptake. This was reversed in the chronic setting in the face of slowed relaxation kinetics. As underlying cause, acutely increased ROS levels were identified to activate Ca/calmodulin-dependent protein kinase II (CaMKII). Accordingly, CaMKII-, but not PKA-dependent phosphorylation sites of the SR Ca release channels (RyR2, at Ser-2814) and phospholamban (at Thr-17) were found to be hyperphosphorylated following IR. Conversely, ROS-scavenging as well as CaMKII-inhibition significantly attenuated CaMKII-activation, disturbed Ca handling, and subsequent cellular dysfunction upon irradiation. Targeted cardiac irradiation induces a biphasic effect on cardiac myocytes Ca handling that is associated with chronic cardiocellular dysfunction. This appears to be mediated by increased oxidative stress and persistently activated CaMKII. Our findings suggest impaired cardiac myocytes Ca handling as a so far unknown mediator of IR-dependent cardiac damage that might be of relevance for radiation-induced cardiac dysfunction.

Original languageEnglish
Article number385
Pages (from-to)N/A
Number of pages15
JournalBasic Research in Cardiology
Volume108
Issue number6
DOIs
Publication statusPublished - 26 Sept 2013

Keywords

  • Irradiation
  • Excitation-contraction coupling
  • Calcium
  • Free radicals
  • CaMKII
  • HEART-FAILURE
  • CARDIOVASCULAR-DISEASE
  • INDUCED CARDIOMYOPATHY
  • DIASTOLIC DYSFUNCTION
  • FAILING MYOCARDIUM
  • MYOCYTES
  • CONTRIBUTES
  • IRRADIATION
  • SUPEROXIDE
  • MORTALITY

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