Abstract
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 beta-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 beta1-adrenergic
receptor. METHODS AND RESULTS: We crossed beta1-adrenergic receptor
transgenic (beta1TG) mice with mice homozygous for a targeted deletion
of the phospholamban gene (PLB-/-). Phospholamban ablation dramatically
enhanced survival of beta1TG mice. The decrease of left ventricular
contractility typically observed in beta1TG mice was reverted back
to normal by phospholamban ablation. Cardiac hypertrophy and fibrosis
were significantly inhibited in beta1TG/PLB-/- mice compared with
beta1TG 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 beta1TG mice. In beta1TG/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 beta1TG
mice through ablation of phospholamban resulted in a rescue of functional,
morphological, and molecular characteristics of heart failure in
beta1-adrenergic receptor-transgenic mice. These results imply altered
calcium handling as critical for the detrimental effects of beta1-adrenergic
signaling.
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