Calcium/calmodulin‐dependent protein kinase II links hepatic cytosolic calcium release and apoptosis after burn injury

Liver integrity is essential to survival post burn as impaired liver function worsens prognosis in burn patients. Hepatocytes isolated after thermal injury have increased cytosolic calcium which is associated with depletion of endoplasmic reticulum (ER) calcium stores which is associated with upregulation of proteins involved in the ER unfolded protein response (UPR) pathway and activation of Jun N‐terminal kinase (JNK). Recently, it has been shown that UPR induced increases in cytosolic calcium due to depletion of ER calcium stores can activate calcium/calmodulin‐dependent protein kinase II (CaMKII). Further, CaMKII was shown to play a pro‐apoptotic role via JNK‐mediated upregulation of Fas receptor. We therefore hypothesize that activation of CaMKII provides a mechanistic link between increases in cytosolic calcium and hepatic apoptosis after burn injury. As a model system, we employed the use of the 60% total burn surface area burn model on rats that recapitulates human clinical findings. We have found that CaMKII is activated one to three hours post burn. Activation of CaMKII is associated with increased JNK activity, upregulation of Fas signaling, and subsequent Fas‐mediated apoptosis. We conclude that burn‐induced increases in hepatic cytosolic calcium activate CaMKII and lead to Fas‐mediated apoptosis. This work is supported by NIH/NIGMS grant GM081685 and Shiners grants 8660 and 8640