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

Abstract

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. 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. 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.