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

Citation
Y. Sato et al., Rescue of contractile parameters and myocyte hypertrophy in calsequestrin overexpressing myocardium by phospholamban ablation, J BIOL CHEM, 276(12), 2001, pp. 9392-9399
Citations number
53
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
12
Year of publication
2001
Pages
9392 - 9399
Database
ISI
SICI code
0021-9258(20010323)276:12<9392:ROCPAM>2.0.ZU;2-8
Abstract
Cardiac-specific overexpression of murine cardiac calsequestrin results in depressed cardiac contractile parameters, low Ca2+-induced Ca2+ release fro m sarcoplasmic reticulum (SR) and cardiac hypertrophy in transgenic mice. T o 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 i n calsequestrin overexpressing mice led to reversal of the depressed cardia c contractile parameters in Langendorff-perfused hearts or in vivo. This wa s associated with increases of SR Ca2+ storage, assessed by caffeine-induce d Na+-Ca2+ exchanger currents. The inactivation time of the L-type Ca2+ cur rent (I-Ca) which has an inverse correlation with Ca2+-induced SR Ca2+ rele ase, and the relation between the peak current density and half-inactivatio n time were also normalized, indicating a restoration in the ability of I-C a to trigger SR Ca2+ release. The prolonged action potentials in calsequest rin overexpressing cardiomyocytes also reversed to normal upon phospholamba n 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 pho spholamban function may pr-event or overcome functional and remodeling defe cts in hypertrophied hearts.