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(Circulation. 2004;109:1154-1160.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Altered Calcium Handling Is Critically Involved in the Cardiotoxic Effects of Chronic ß-Adrenergic Stimulation

Stefan Engelhardt, MD, PhD; Lutz Hein, MD; Vitaly Dyachenkow; Evangelia G. Kranias, PhD; Gerrit Isenberg, MD; Martin J. Lohse, MD

From the Institute of Pharmacology and Toxicology (S.E., L.H., M.J.L.), University of Wuerzburg, Germany; Institute of Physiology (V.D., G.I.), Martin-Luther-University Halle, Germany; and Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati College of Medicine, Cincinnati, Ohio.

Correspondence to Stefan Engelhardt, Rudolf-Virchow-Center for Experimental Biomedicine, DFG Forschungszentrum der Universitaet Wuerzburg, Versbacher Straße 9, 97078 Wuerzburg, Germany. E-mail stefan.engelhardt{at}virchow.uni-wuerzburg.de

Received July 18, 2003; revision received October 24, 2003; accepted October 28, 2003.

Background— Chronic adrenergic stimulation leads to cardiac hypertrophy and heart failure in experimental models and contributes to the progression of heart failure in humans. The pathways mediating the detrimental effects of chronic ß-adrenergic stimulation are only partly understood. We investigated whether genetic modification of calcium handling through deletion of phospholamban in mice would affect the development of heart failure in mice with transgenic overexpression of the ß₁-adrenergic receptor.

Methods and Results— We crossed ß₁-adrenergic receptor transgenic (ß₁TG) mice with mice homozygous for a targeted deletion of the phospholamban gene (PLB^-/-). Phospholamban ablation dramatically enhanced survival of ß₁TG mice. The decrease of left ventricular contractility typically observed in ß₁TG mice was reverted back to normal by phospholamban ablation. Cardiac hypertrophy and fibrosis were significantly inhibited in ß₁TG/PLB^-/- mice compared with ß₁TG mice, and the heart failure–specific gene expression pattern was normalized. Analysis of intracellular calcium transients revealed increased diastolic calcium levels and decreased rate constants of diastolic calcium decline in ß₁TG mice. In ß₁TG/PLB^-/- mice, diastolic calcium concentration was normal and rate constants of diastolic calcium decline were greater than in wild-type mice.

Conclusions— We conclude that modification of abnormal calcium handling in ß₁TG mice through ablation of phospholamban resulted in a rescue of functional, morphological, and molecular characteristics of heart failure in ß₁-adrenergic receptor–transgenic mice. These results imply altered calcium handling as critical for the detrimental effects of ß₁-adrenergic signaling.

Key Words: calcium • heart failure • sarcoplasmic reticulum • hypertrophy • heart failure

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