title: Imbalance between CaM kinase II and calcineurin activities impairs caffeine-induced calcium release in hypertrophic cardiomyocytes.
abstract: Cardiac hypertrophy impairs Ca(2+) handling in the sarcoplasmic reticulum, thereby impairing cardiac contraction. To identify the mechanisms underlying impaired Ca(2+) release from the sarcoplasmic reticulum in hypertrophic cardiomyocytes, we assessed Ca(2+)-dependent signaling and the phosphorylation of phospholamban, which regulates Ca(2+) uptake during myocardial relaxation and is in turn regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and calcineurin. In cultured rat cardiomyocytes, treatment with endothelin-1, angiotensin II, and phenylephrine-induced hypertrophy and increased CaMKII autophosphorylation and calcineurin expression. The calcineurin level reached its maximum at 72h and remained elevated for at least 96h after endothelin-1 or angiotensin II treatment. By contrast, CaMKII autophosphorylation, phospholamban phosphorylation, and caffeine-induced Ca(2+) mobilization all peaked 48h after these treatments. By 96h after treatment, CaMKII autophosphorylation and phospholamban phosphorylation had returned to baseline, and caffeine-induced Ca(2+) mobilization was impaired relative to baseline. A similar biphasic change was observed in dystrophin levels in endothelin-1-induced hypertrophic cardiomyocytes, and treatment with the novel CaM antagonists DY-9760e and DY-9836 significantly inhibited the hypertrophy-induced dystrophin breakdown. Taken together, the abnormal Ca(2+) regulation in cardiomyocytes following hypertrophy is in part mediated by an imbalance in calcineurin and CaMKII activities, which leads to abnormal phospholamban activity.
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: Ying-Mei
authors: YM
authors: Lu
authors: Norifumi
authors: N
authors: Shioda
authors: Feng
authors: F
authors: Han
authors: Shigeki
authors: S
authors: Moriguchi
authors: Jiro
authors: J
authors: Kasahara
authors: Yasufumi
authors: Y
authors: Shirasaki
authors: Zheng-Hong
authors: ZH
authors: Qin
authors: Kohji
authors: K
authors: Fukunaga
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D000099211:Phospholamban
chemical_list: D000804:Angiotensin II; D019703:Calcineurin; D002118:Calcium; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019332:Endothelin-1; D007191:Indazoles; D010656:Phenylephrine; D000099211:Phospholamban; C109602:3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate