Intracellular Na+ overload causes oxidation of CaMKII and leads to Ca2Â + mishandling in isolated ventricular myocytes

An increase of late Na+ current (INaL) in cardiac myocytes can raise the cytosolic Na+ concentration and is associated with activation of Ca2 +/calmodulin-dependent protein kinase II (CaMKII) and alterations of mitochondrial metabolism and Ca2 + handling by sarcoplasmic reticulum (SR). We tested the hypothesis that augmentation of INaL can increase mitochondrial reactive oxygen species (ROS) production and oxidation of CaMKII, resulting in spontaneous SR Ca2 + release and increased diastolic Ca2 + in myocytes. Increases of INaL and/or of the cytosolic Na+ concentration led to mitochondrial ROS production and oxidation of CaMKII to cause dysregulation of Ca2 + handling in rabbit cardiac myocytes.