Key result
Cardiac irradiation acutely enhances but chronically impairs myocyte contractility via oxidative stress and CaMKII.
Why the study?
Ionizing radiation during chest radiotherapy induces reactive oxygen species that may impair cardiac myocytes' Ca handling and contribute to cardiac dysfunction.
Does ionizing radiation impair cardiac myocytes' Ca handling and contribute to cardiocellular dysfunction in mouse models?
Does ionizing radiation impair cardiac myocytes' Ca handling and contribute to cardiocellular dysfunction in mouse models?
Ionizing radiation induces a biphasic effect on cardiac myocyte calcium handling via ROS and CaMKII activation, leading to chronic cardiocellular dysfunction.
IR may impair myocyte Ca handling via ROS-CaMKII; leaves open clinical relevance for radiation cardiotoxicity.
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 ~1 h) as well as chronically (after ~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.
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Sag et al. (2013) studied Radiation-induced cardiac dysfunction. Ionizing radiation vs. Sham irradiation (0 Gy) was evaluated on Cardiac myocyte Ca handling and left ventricular contractility. Targeted cardiac irradiation induced a biphasic effect on cardiac myocytes Ca handling, with acutely enhanced but chronically decreased contractility mediated by increased oxidative stress and persistently activated CaMKII.
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