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

Y Sato1, H Kiriazis, A Yatani

  • 1Department of Pharmacology and Cell Biophysics, and Division of Cardiology, University of Cincinnati, Ohio 45267, USA.

The Journal of Biological Chemistry
|December 25, 2000
PubMed

Insights

Overexpressing cardiac calsequestrin impairs heart function. Inhibiting phospholamban activity in these mice restored cardiac contractility and reversed hypertrophy, suggesting a therapeutic target.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Physiology

Background:

  • Cardiac-specific overexpression of calsequestrin in mice leads to impaired cardiac contractility, reduced sarcoplasmic reticulum (SR) Ca(2+) release, and cardiac hypertrophy.
  • Phospholamban regulates SR Ca(2+) uptake and release, influencing cardiac function.

Purpose of the Study:

  • To investigate if inhibiting phospholamban activity can ameliorate the cardiac dysfunction and hypertrophy caused by calsequestrin overexpression.
  • To test the hypothesis that phospholamban ablation rescues phenotypic alterations in calsequestrin-overexpressing mice.

Main Methods:

  • Cross-breeding calsequestrin-overexpressing mice with phospholamban-knockout mice.
  • Assessing cardiac contractile parameters in Langendorff-perfused hearts and in vivo.
  • Measuring SR Ca(2+) storage via caffeine-induced Na(+)-Ca(2+) exchanger currents.
  • Analyzing L-type Ca(2+) current (I(Ca)) inactivation kinetics and action potential duration in cardiomyocytes.
  • Evaluating the expression of atrial natriuretic factor and alpha-skeletal actin mRNA and ventricular myocyte size.

Main Results:

  • Phospholamban ablation reversed depressed cardiac contractile parameters and normalized SR Ca(2+) storage.
  • The inactivation time of I(Ca) and its relationship with peak current density were normalized, indicating restored Ca(2+)-induced SR Ca(2+) release.
  • Action potential duration in cardiomyocytes returned to normal.
  • Expression of atrial natriuretic factor and alpha-skeletal actin mRNA, and ventricular myocyte size were restored.

Conclusions:

  • Attenuation of phospholamban function can prevent or overcome functional and remodeling defects in hypertrophied hearts caused by calsequestrin overexpression.
  • Inhibiting phospholamban activity represents a potential therapeutic strategy for heart failure with preserved ejection fraction and hypertrophy.

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