Intracellular Na⁺ overload causes oxidation of CaMKII and leads to Ca²⁺ mishandling in isolated ventricular myocytes

An increase of late Na⁺ current (I_NaL) 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 I_NaL 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 I_NaL 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.