Published Online
on February 16, 2004

A more recent version of this article appeared on March 9, 2004

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Submitted on July 18, 2003
Revised on October 24, 2003
Accepted on October 28, 2003

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

Stefan Engelhardt MD, PhD^*, Lutz Hein MD, Vitaly Dyachenkow; , Evangelia G. Kranias PhD, Gerrit Isenberg MD, and 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.

^* To whom correspondence should be addressed. E-mail: stefan.engelhardt{at}virchow.uni-wuerzburg.de.

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 -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 ₁-adrenergic receptor.

Methods and Results--We crossed ₁-adrenergic receptor transgenic (₁TG) mice with mice homozygous for a targeted deletion of the phospholamban gene (PLB^-/-). Phospholamban ablation dramatically enhanced survival of ₁TG mice. The decrease of left ventricular contractility typically observed in ₁TG mice was reverted back to normal by phospholamban ablation. Cardiac hypertrophy and fibrosis were significantly inhibited in ₁TG/PLB^-/- mice compared with ₁TG 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 ₁TG mice. In ₁TG/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 ₁TG mice through ablation of phospholamban resulted in a rescue of functional, morphological, and molecular characteristics of heart failure in ₁-adrenergic receptor-transgenic mice. These results imply altered calcium handling as critical for the detrimental effects of ₁-adrenergic signaling.

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

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