Imbalance between CaM kinase II and calcineurin activities impairs caffeine-induced calcium release in hypertrophic cardiomyocytes

Ying Mei Lu, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Jiro Kasahara, Yasufumi Shirasaki, Zheng Hong Qin, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


Cardiac hypertrophy impairs Ca2+ handling in the sarcoplasmic reticulum, thereby impairing cardiac contraction. To identify the mechanisms underlying impaired Ca2+ release from the sarcoplasmic reticulum in hypertrophic cardiomyocytes, we assessed Ca2+-dependent signaling and the phosphorylation of phospholamban, which regulates Ca2+ uptake during myocardial relaxation and is in turn regulated by Ca2+/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 72 h and remained elevated for at least 96 h after endothelin-1 or angiotensin II treatment. By contrast, CaMKII autophosphorylation, phospholamban phosphorylation, and caffeine-induced Ca2+ mobilization all peaked 48 h after these treatments. By 96 h after treatment, CaMKII autophosphorylation and phospholamban phosphorylation had returned to baseline, and caffeine-induced Ca2+ 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 Ca2+ regulation in cardiomyocytes following hypertrophy is in part mediated by an imbalance in calcineurin and CaMKII activities, which leads to abnormal phospholamban activity.

Original languageEnglish
Pages (from-to)1727-1737
Number of pages11
JournalBiochemical Pharmacology
Issue number12
Publication statusPublished - 2007 Dec 15


  • Calcineurin
  • CaMKII
  • Cardiomyocyte
  • DY-9760e
  • Hypertrophy
  • Phospholamban


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