Activation of CaMKII_δC is a common intermediate of diverse death stimuli-induced heart muscle cell apoptosis

Ca²⁺-calmodulin-dependent protein kinase II (CaMKII) is expressed in many mammalian cells, with the δ isoform predominantly expressed in cardiomyocytes. Previous studies have shown that inhibition of CaMKII protects cardiomyocytes against β₁-adrenergic receptor-mediated apoptosis. However, it is unclear whether activation of CaMKII is sufficient to cause cardiomyocyte apoptosis and whether CaMKII signaling is important in heart muscle cell apoptosis mediated by other stimuli. Here, we specifically enhanced or suppressed CaMKII activity using adenoviral gene transfer of constitutively active (CA-CaMKII_δC) or dominant negative (DN-CaMKII_δC) mutants of CaMKII_δC in cultured adult rat cardiomyocytes. Expression of CA-CaMKII_δC promoted cardiomyocyte apoptosis that was associated with increased mitochondrial cytochrome c release and attenuated by co-expression of Bcl-X _L. Importantly, isoform-specific suppression of CaMKII _δC with the DN-CaMKII_δC mutant similar to nonselective CaMKII inhibition by the pharmacological inhibitors (KN-93 or AIP) not only prevented CA-CaMKII_δC-mediated apoptosis but also protected cells from multiple death-inducing stimuli. Thus, activation of CaMKII_δC constitutes a common intermediate by which various death-inducing stimuli trigger cardiomyocyte apoptosis via the primary mitochondrial death pathway.