Abstract 16113: Upregulation of Cardiac β3-Adrenergic Signaling Promotes Heart Failure Progression
Background. The negative inotrope and upregulation of β3-adrenergic receptors (AR) in failing human and animal hearts suggest a direct and contributing role of cardiac β3-AR activation on heart failure (HF) progression. However, its precise role is still being debated. We hypothesize that up-regulation of β3-AR is detrimental and chronic β3-AR blockade may limit or prevent the progression of HF.
Methods. We determined Left ventricular (LV) and myocyte functional response and β1- and β3-AR expressions in 3 groups of rats (6/group) for a period of 4 months: 1) Isoproterenol (ISO)-treated, 4 months after receiving ISO (170 mg/kg, sq, for 2 days); 2) ISO/β3-ANT, two months after receiving ISO, L-748,337, a selective β3-AR antagonist (β3-ANT) (10-7 M/kg/day by implanted osmotic mini pump) was initiated after established HF and was given for 2 months; and 3) sham controls.
Results. Compared with controls, ISO-treated rats had HF onset at one month after ISO and progressed to severe HF at 4 months. Plasma norepinephrine (NE, 1482 vs 247 pg/ml) increased 6 fold. Both stroke volume (SV) and ejection fraction (EF, 32% vs 61%) decreased more than 48%, and LV end-diastolic pressure (PED, 15.4 vs 6.0 mmHg) doubled, parallel with 48% reductions in cell contraction (dL/dtmax,78 vs 149 μm/s) and relaxation (dR/dtmax, 66 vs 128 μm/s) and a much less increase in dL/dtmax(30% vs 74%) in response to superfusion of ISO (10-8 M). These changes were associated with significantly decreased β1-AR mRNA (0.30 vs 0.64) and protein levels (0.36 vs 0.62), but increased β3-AR mRNA (1.29 vs 0.52) and protein levels (0.35 vs 0.18). Treatment with β3-ANT significantly decreased PED and plasma NE (191 pg/ml). Both SV and EF (59%) increased to more than 76% from ISO-treated values. The signal ratios of β1-AR mRNA (0.61) and β3-AR mRNA (0.59) remained close to control levels. ISO-induced increase in dL/dtmax (75%) was also significantly augmented.
Conclusion. Chronic β3-ANT prevented plasma norepinephrine elevations and causes normalization of β1- and β3-AR gene expression, restores normal responsiveness of myocyte to β-AR stimulation, and leads to regression of LV and myocyte dysfunction in a rat model of progressive HF. Thus, β3-AR blocker may provide a new therapeutic strategy for the treatment of HF.
Author Disclosures: X. Zhang: None. T. Li: None. H. Cheng: None. P. Zhou: None. M. Callahan: None. C. Cheng: None.
- © 2015 by American Heart Association, Inc.