Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo

Yingbo Yang, Wei Zhong Zhu, Mei Ling Joiner, Rong Zhang, Carmine V. Oddis, Yue Hou, Jinying Yang, Edward E. Price, Linda Gleaves, Mesut Eren, Gemin Ni, Douglas E. Vaughan, Rui Ping Xiao, Mark E. Anderson

Research output: Contribution to journalArticle

106 Scopus citations

Abstract

Inhibition of the multifunctional Ca2+/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 Ca2+ 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 Ca2+ 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 Ca2+-dependent pathway. AC3-I and AC3-C mice were bred into a PLN-/- background. Loss of PLN increased and equalized SR Ca2+ 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 Ca2+ content by PLN contributes to the antiapoptotic mechanism of CaMKII inhibition.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume291
Issue number6
DOIs
StatePublished - 2006
Externally publishedYes

    Fingerprint

Keywords

  • Isoproterenol
  • Myocardial infarction
  • Phospholamban
  • Programmed cell death

ASJC Scopus subject areas

  • Physiology

Cite this

Yang, Y., Zhu, W. Z., Joiner, M. L., Zhang, R., Oddis, C. V., Hou, Y., Yang, J., Price, E. E., Gleaves, L., Eren, M., Ni, G., Vaughan, D. E., Xiao, R. P., & Anderson, M. E. (2006). Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo. American Journal of Physiology - Heart and Circulatory Physiology, 291(6). https://doi.org/10.1152/ajpheart.00353.2006