Myocardial death and dysfunction after ischemia-reperfusion injury require CaMKIIδ oxidation

Reactive oxygen species (Ros) contribute to myocardial death during ischemia-reperfusion (I/R) injury, but detailed knowledge of molecular pathways connecting Ros to cardiac injury is lacking. Activation of the Ca2+/calmodulin-dependent protein kinase II (CaMKIIδ) is implicated in myocardial death, and CaMKII can be activated by Ros (ox-CaMKII) through oxidation of regulatory domain methionines (Met281/282). We examined I/R injury in mice where CaMKIIδ was made resistant to Ros activation by knock-in replacement of regulatory domain methionines with valines (MMVV). We found reduced myocardial death, and improved left ventricular function 24 hours after I/R injury in MMVV in vivo and in vitro compared to Wt controls. Loss of Atp sensitive K+ channel (KAtp) current contributes to I/R injury, and CaMKII promotes sequestration of KAtp from myocardial cell membranes. KAtp current density was significantly reduced by H2o2 in Wt ventricular myocytes, but not in MMVV, showing ox-CaMKII decreases KATP availability. Taken together, these findings support a view that ox-CaMKII and KATP are components of a signaling axis promoting I/R injury by Ros.