Rescue of contractile parameters and myocyte hypertrophy in calsequestrin overexpressing myocardium by phospholamban ablation.
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.
Sato
Y
Y
Department of Pharmacology and Cell Biophysics, and Division of Cardiology, University of Cincinnati, Ohio 45267, USA.
Kiriazis
H
H
Yatani
A
A
Schmidt
A G
AG
Hahn
H
H
Ferguson
D G
DG
Sako
H
H
Mitarai
S
S
Honda
R
R
Mesnard-Rouiller
L
L
Frank
K F
KF
Beyermann
B
B
Wu
G
G
Fujimori
K
K
Dorn
G W
GW
Kranias
E G
EG
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology; D002155:Calsequestrin / Q000378:metabolism*; D006332:Cardiomegaly; D006321:Heart / Q000187:drug effects; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D000099211:Phospholamban
D015056:1-Methyl-3-isobutylxanthine; D009320:Atrial Natriuretic Factor; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D007545:Isoproterenol; D000099211:Phospholamban