title: Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo.
abstract: Inhibition of the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) or depletion of sarcoplasmic reticulum (SR) Ca(2+) stores protects against apoptosis from excessive isoproterenol (Iso) stimulation in cultured ventricular myocytes, suggesting that CaMKII inhibition could be a novel approach to reducing cell death in conditions of increased adrenergic tone, such as myocardial infarction (MI), in vivo. We used mice with genetic myocardial CaMKII inhibition due to transgenic expression of a highly specific CaMKII inhibitory peptide (AC3-I) to test whether CaMKII was important for apoptosis in vivo. A second line of mice expressed a scrambled, inactive form of AC3-I (AC3-C). AC3-C and wild-type (WT) littermates were used as controls. AC3-I mice have reduced SR Ca(2+) content and are resistant to Iso- and MI-induced apoptosis compared with AC3-C and WT mice. Phospholamban (PLN) is a target for modulation of SR Ca(2+) content by CaMKII. PLN(-/-) mice have increased susceptibility to Iso-induced apoptosis. Verapamil pretreatment prevented Iso-induced apoptosis in PLN(-/-) mice, indicating the involvement of a Ca(2+)-dependent pathway. AC3-I and AC3-C mice were bred into a PLN(-/-) background. Loss of PLN increased and equalized SR Ca(2+) content in AC3-I, AC3-C, and WT mice and abolished the resistance to apoptosis in AC3-I mice after MI. There was a trend (P = 0.07) for increased Iso-induced apoptosis in AC3-I mice lacking PLN compared with AC3-I mice with PLN. These findings indicate CaMKII is proapoptotic in vivo and suggest that regulation of SR Ca(2+) content by PLN contributes to the antiapoptotic mechanism of CaMKII inhibition.
authors.affiliation: Dept. of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Yang
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Zhu
authors.forename: Mei-ling
authors.initials: ML
authors.lastname: Joiner
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Carmine V
authors.initials: CV
authors.lastname: Oddis
authors.forename: Yue
authors.initials: Y
authors.lastname: Hou
authors.forename: Jinying
authors.initials: J
authors.lastname: Yang
authors.forename: Edward E
authors.initials: EE
authors.lastname: Price
authors.forename: Linda
authors.initials: L
authors.lastname: Gleaves
authors.forename: Mesut
authors.initials: M
authors.lastname: Eren
authors.forename: Gemin
authors.initials: G
authors.lastname: Ni
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D002118:Calcium; D002121:Calcium Channel Blockers; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol; D014700:Verapamil; D000099211:Phospholamban; C514810:Camk2n2 protein, mouse