Rescue of contractile parameters and myocyte hypertrophy in calsequestrin overexpressing myocardium by phospholamban ablation
| Autor: | Atsuko Yatani, Beate Beyermann, Ritsu Honda, Gerald W. Dorn, Evangelia G. Kranias, Laurence Mesnard-Rouiller, Albrecht Schmidt, Guangyu Wu, Konrad Frank, Helen Kiriazis, Harvey S. Hahn, Hidenori Sako, Yoji Sato, Donald G. Ferguson, Sayaka Mitarai, Kannosuke Fujimori |
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| Rok vydání: | 2000 |
| Předmět: |
Genetically modified mouse
medicine.medical_specialty Patch-Clamp Techniques medicine.medical_treatment Cardiomegaly Calsequestrin Biochemistry Mice In vivo Internal medicine 1-Methyl-3-isobutylxanthine medicine Animals Myocyte hypertrophy Molecular Biology Mice Knockout Chemistry Endoplasmic reticulum Myocardium Calcium-Binding Proteins Isoproterenol Peak current Heart Cell Biology musculoskeletal system Ablation Immunohistochemistry Myocardial Contraction Phospholamban Sarcoplasmic Reticulum Endocrinology cardiovascular system tissues Atrial Natriuretic Factor |
| Zdroj: | The Journal of biological chemistry. 276(12) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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