Rescue of Contractile Parameters and Myocyte Hypertrophy in Calsequestrin Overexpressing Myocardium by Phospholamban Ablation

Yoji Sato, Helen Kiriazis, Atsuko Yatani, Albrecht G. Schmidt, Harvey Hahn, Donald G. Ferguson, Hidenori Sako, Sayaka Mitarai, Ritsu Honda, Laurence Mesnard-Rouiller, Konrad F. Frank, Beate Beyermann, Guangyu Wu, Kannosuke Fujimori, Gerald W. Dorn, Evangelia G. Kranias

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

Cardiac-specific overexpression of murine cardiac calsequestrin results in depressed cardiac contractile parameters, low Ca2+-induced Ca 2+ release from sarcoplasmic reticulum (SR) and cardiac hypertrophy in transgenic mice. To test the hypothesis that inhibition of phospholamban activity may rescue some of these phenotypic alterations, the calsequestrin overexpressing mice were cross-bred with phospholamban-knockout mice. Phospholamban ablation in calsequestrin overexpressing mice led to reversal of the depressed cardiac contractile parameters in Langendorff-perfused hearts or in vivo. This was associated with increases of SR Ca2+ storage, assessed by caffeine-induced Na+-Ca2+ exchanger currents. The inactivation time of the L-type Ca2+ current (ICa) which has an inverse correlation with Ca2+-induced SR Ca 2+ release, and the relation between the peak current density and half-inactivation time were also normalized, indicating a restoration in the ability of ICa to trigger SR Ca2+ release. The prolonged action potentials in calsequestrin overexpressing cardiomyocytes also reversed to normal upon phospholamban ablation. Furthermore, ablation of phospholamban restored the expression levels of atrial natriuretic factor and α-skeletal actin mRNA as well as ventricular myocyte size. These results indicate that attenuation of phospholamban function may prevent or overcome functional and remodeling defects in hypertrophied hearts.

Original languageEnglish (US)
Pages (from-to)9392-9399
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number12
DOIs
StatePublished - Mar 23 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Sato, Y., Kiriazis, H., Yatani, A., Schmidt, A. G., Hahn, H., Ferguson, D. G., Sako, H., Mitarai, S., Honda, R., Mesnard-Rouiller, L., Frank, K. F., Beyermann, B., Wu, G., Fujimori, K., Dorn, G. W., & Kranias, E. G. (2001). Rescue of Contractile Parameters and Myocyte Hypertrophy in Calsequestrin Overexpressing Myocardium by Phospholamban Ablation. Journal of Biological Chemistry, 276(12), 9392-9399. https://doi.org/10.1074/jbc.M006889200