Abstract 14636: Upregulation of Cardiac β3-Adrenergic Signaling Promotes Heart Failure Progression: Evidence from Chronic β3-Adrenoceptor (AR) deficiency or β3-AR Blockade Mice
Background: Heart failure (HF) is associated with the upregulation of β3-adrenergic receptor (AR)-mediated cardiac inhibitory pathway. This suggests cardiac β3-AR activation may contribute to HF progression and be a therapeutic target. We hypothesize that if upregulation of β3-AR is maladaptive, isoproterenol (ISO)-induced HF will be prevented in β3-AR knockout (β3KO) mice or reversed with chronic treatment of β3-AR antagonist (β3-ANT).
Methods: We compared left ventricular (LV) and myocyte function and myocyte β-AR and SR Ca2+-ATPase (SERCA2a) protein expression over 16 weeks in 5 groups (6/group) of male mice. Three ISO-treated groups: wild-type (WT) and β3KO mice received ISO (170 mg/kg sq for 2 days), and one group WT mice after ISO injection for 12 weeks (W), L-748,337, a selective β3-ANT (10-7 M/kg/day sq by mini pump) was initiated and was given for 4W. Two control groups of WT and β3KO mice received saline.
Results: Compared with controls and ISO-treated β3KO, only ISO-treated WT (ISO/WT) mice had HF onset at 4W after ISO and progressed to severe HF at 16W with significantly elevated plasma levels of norepinephrine and increased LV myocyte protein levels of β3-AR (0.34 vs 0.12), but significantly decreased β1-AR (0.32 vs 0.62) and SERCA 2a (0.25 vs 0.68). These changes were followed by a progressive fall in LV contractility (EES) (0.7 vs 1.2 mmHg/μl); reductions in the peak velocity of myocyte shortening (79.4 vs 162.8 μm/s) and relengthening (73.5 vs 146.4 μm/s) and decreased peak [Ca2+]iT (0.15 vs 0.29) accompanied by a diminished myocyte inotropic response to β-AR agonist, ISO (10-8 M). Chronic β3-ANT prevented the HF-induced decreases in LV and myocyte contraction, relaxation, peak [Ca2+]iT, and restored normal myocyte contractile response to ISO stimulation. With ISO/WT plus β3-ANT, levels of plasma norepinephrine, myocyte β1-AR and SERCA2a protein expression were similar to that obtained from ISO/β3KO mice and all were remained close to control values of WT and β3KO.
Conclusions: β3-AR deficiency prevented and chronic β3-ANT reversed HF-caused downregulation of myocyte β1-ARs and SERCA2a leads to the preservation of LV and myocyte function, [Ca2+]iT, and β-AR responsiveness. Thus, blocking β3-AR may provide a new strategy for the treatment of HF.
Author Disclosures: H. Cheng: None. P. Zhou: None. T. Li: None. D. Kitzman: None. M.F. Callahan: None. S. Masutani: None.
- © 2014 by American Heart Association, Inc.