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Altered calcium handling is critically involved in the cardiotoxic effects of chronic beta-adrenergic stimulation

Stefan Engelhardt1, Lutz Hein, Vitaly Dyachenkow

  • 1Institute of Pharmacology and Toxicology, of Wuerzburg, Germany. stefan.engelhardt@virchow.uni-wuerzburg.de

Circulation
|February 18, 2004
PubMed
Abstract

Insights

Ablating phospholamban in mice with beta1-adrenergic receptor overexpression rescued heart failure. This genetic modification normalized cardiac function, structure, and gene expression, highlighting calcium handling

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Genetic Engineering

Background:

  • Chronic beta-adrenergic stimulation contributes to cardiac hypertrophy and heart failure.
  • Pathways mediating detrimental effects of beta-adrenergic stimulation are not fully understood.
  • Investigating genetic modification of calcium handling in heart failure models.

Purpose of the Study:

  • To determine if deleting phospholamban affects heart failure development in beta1-adrenergic receptor-transgenic mice.
  • To investigate the role of calcium handling in beta-adrenergic receptor-induced heart failure.

Main Methods:

  • Crossed beta1-adrenergic receptor transgenic (beta1TG) mice with phospholamban-deficient (PLB-/-) mice.
  • Assessed survival, cardiac function (left ventricular contractility), cardiac hypertrophy, fibrosis, and gene expression.
  • Analyzed intracellular calcium transients and diastolic calcium levels.

Main Results:

  • Phospholamban ablation significantly improved survival in beta1TG mice.
  • Cardiac function, hypertrophy, and fibrosis were normalized in beta1TG/PLB-/- mice.
  • Abnormal intracellular calcium handling in beta1TG mice was corrected by phospholamban ablation.

Conclusions:

  • Modifying calcium handling by ablating phospholamban rescues heart failure characteristics in beta1-adrenergic receptor-transgenic mice.
  • Altered calcium handling is critical for the detrimental effects of beta1-adrenergic signaling in the heart.
  • Phospholamban deficiency protects against beta1-adrenergic receptor-induced cardiac dysfunction.

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