title: Activation of CaMKIIdeltaC is a common intermediate of diverse death stimuli-induced heart muscle cell apoptosis.
abstract: Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is expressed in many mammalian cells, with the delta isoform predominantly expressed in cardiomyocytes. Previous studies have shown that inhibition of CaMKII protects cardiomyocytes against beta(1)-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(deltaC)) or dominant negative (DN-CaMKII(deltaC)) mutants of CaMKII(deltaC) in cultured adult rat cardiomyocytes. Expression of CA-CaMKII(deltaC) 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(deltaC) with the DN-CaMKII(deltaC) mutant similar to nonselective CaMKII inhibition by the pharmacological inhibitors (KN-93 or AIP) not only prevented CA-CaMKII(deltaC)-mediated apoptosis but also protected cells from multiple death-inducing stimuli. Thus, activation of CaMKII(deltaC) constitutes a common intermediate by which various death-inducing stimuli trigger cardiomyocyte apoptosis via the primary mitochondrial death pathway.
authors.affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
authors.forename: Anthony Yiu-Ho
authors.initials: AY
authors.lastname: Woo
authors.forename: Dongmei
authors.initials: D
authors.lastname: Yang
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.forename: Michael T
authors.initials: MT
authors.lastname: Crow
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression; D008929:Mitochondria, Heart / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology*; D047428:Protein Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D045304:Cytochromes c; D047428:Protein Kinase Inhibitors; D018342:Receptors, Adrenergic, beta-1; D013449:Sulfonamides; D051020:bcl-X Protein; C072105:KN 93; D000096926:Benzenesulfonamides