Rescue of contractile parameters and myocyte hypertrophy in calsequestrin overexpressing myocardium by phospholamban ablation.

Abstract

Cardiac-specific overexpression of murine cardiac calsequestrin results in depressed cardiac contractile parameters, low Ca(2+)-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 Ca(2+) storage, assessed by caffeine-induced Na(+)-Ca(2+) exchanger currents. The inactivation time of the L-type Ca(2+) current (I(Ca)), which has an inverse correlation with Ca(2+)-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 I(Ca) to trigger SR Ca(2+) 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 alpha-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.

• Authors: Y Sato, H Kiriazis, A Yatani, A G Schmidt, H Hahn, D G Ferguson, H Sako, S Mitarai, R Honda, L Mesnard-Rouiller, K F Frank, B Beyermann, G Wu, K Fujimori, G W Dorn 2nd, E G Kranias
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 12 Pg. 9392-9 (Mar 23 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11115498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calcium-Binding Proteins
• Calsequestrin
• phospholamban
• Atrial Natriuretic Factor
• Isoproterenol
• 1-Methyl-3-isobutylxanthine

Topics

• 1-Methyl-3-isobutylxanthine (pharmacology)
• Animals
• Atrial Natriuretic Factor (biosynthesis)
• Calcium-Binding Proteins (genetics, physiology)
• Calsequestrin (metabolism)
• Cardiomegaly
• Heart (drug effects)
• Immunohistochemistry
• Isoproterenol (pharmacology)
• Mice
• Mice, Knockout
• Myocardial Contraction
• Myocardium (cytology, metabolism)
• Patch-Clamp Techniques
• Sarcoplasmic Reticulum (metabolism)