Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy

Abstract

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.

Figure 1

Histology of cross-bred mouse hearts. (a) Representative cross-sections of the hearts from HCM × β₂AR offspring: panel 1, NTG; panel 2, HCM; panel 3, β₂AR; panel 4, HCM/β₂AR. (b) HCM × βARKct offspring: panel 1, NTG; panel 2, HCM; panel 3, βARKct; panel 4, HCM/βARKct. (c) HCM × PLB-null offspring: panel 1, NTG; panel 2, HCM; panel 3, PLB-null; panel 4, HCM/PLB-null. Magnification, ×5.

Figure 2

Histology of cross-bred mouse hearts. (a) HCM × β₂AR offspring: panel 1, NTG; panel 2, HCM; panel 3, β₂AR; panel 4, HCM/β₂AR. (b) HCM × βARKct offspring: panel 1, NTG; panel 2, HCM; panel 3, βARKct; panel 4, HCM/βARKct. (c) HCM × PLB-null offspring: panel 1, NTG; panel 2, HCM; panel 3, PLB-null; panel 4, HCM/PLB-null. Magnification ×250.

Figure 3

Systolic function of cross-bred mouse hearts as determined by serial echocardiography. (a) HCM × β₂AR mice (NTG, n = 8; HCM, n = 12; β₂AR, n = 7; HCM/β₂AR, n = 4). (b) HCM × βARKct mice (NTG, n = 5; HCM, n = 6; βARKct, n = 8; HCM/βARKct, n = 5). (c) HCM × PLB-null mice (NTG, n = 6; HCM, n = 8; PLB-null, n = 7; HCM/PLB-null, n = 9). ^AP < 0.05 vs. NTG; ANOVA. ^BP < 0.05 vs. HCM; ANOVA.

Figure 4

Treadmill exercise tolerance of cross-bred mice measured as beam breaks per minute. Mice were run five times for 1 hour at 20 m/min, and scores for each animal were averaged. (a) HCM × β₂AR mice (NTG, n = 8; HCM, n = 6; β₂AR, n = 8; HCM/β₂AR, n = 5). (b) HCM × βARKct mice (NTG, n = 6; HCM, n = 8; βARKct, n = 8; HCM/βARKct, n = 8). (c) HCM × PLB-null mice (NTG, n = 8; HCM, n = 7; PLB-null, n = 7; HCM/PLB-null, n = 8). ^AP < 0.01 vs. NTG; ANOVA. ^BP < 0.05 vs. HCM; ANOVA.

Figure 5

Gene expression in cross-bred mouse hearts as assessed by slot blot of RNA extracted from left ventricular myocardium. All signals were normalized to GAPDH expression and are shown as fold of NTG. (a) HCM × β₂AR mice (NTG, n = 8; HCM, n = 10; β₂AR, n = 6; HCM/β₂AR, n = 4). (b) HCM × βARKct mice (NTG, n = 9; HCM, n = 10; βARKct, n = 10; HCM/βARKct, n = 11). (c) HCM × PLB-null mice (NTG, n = 10; HCM, n = 9; PLB-null, n = 10; HCM/PLB-null, n = 10). ^AP < 0.05 vs. NTG; ANOVA. ^BP < 0.01 vs. NTG; ANOVA. ^CP < 0.05 vs. HCM; ANOVA.