Abstract 12986: Is Beta3-Adrenoceptor (AR) a Target for Heart Failure Therapy? Evidence From Beta3-AR Knockout 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.
Methods. In experimental groups, wild type (WT) and β3KO mice received ISO (170 mg/kg sq for 2 days), and, in control groups, WT and β3KO mice received saline (10/group). After 16 weeks (W) of treatment, we compared left ventricular (LV) and myocyte functional and [Ca2+]i transient ([Ca2+]iT) responses and β1- and β3-AR gene expression in the animals.
Results. Compared with controls (C), ISO-treated WT mice had HF onset at 8W and progressed to severe HF at 16W with 5-fold increase in plasma NE (HF: 4050 vs C: 810 pg/ml) and LV dilatation associated with increased myocyte length (ML, 158 vs121 μm) and heart-to-body weight ratio (H/BW, 7.2 vs 4.9 g/kg). Ejection fraction (EF, 36% vs 63%) and LV contractility measured by EES (42%, 2.2 vs 3.8 mmHg/μl) were significantly reduced. There were significant decreases in myocyte contraction (dL/dtmax, 79.4 vs 162.8 μm/s), relaxation (dR/dtmax, 73.5 vs 146.4 μm/s), and peak [Ca2+]iT (0.16 vs 0.31). These changes were associated with about a 56% decrease in β1-AR protein levels (0.25 vs 0.57), but a 192% increase in β3-AR protein levels (0.79 vs 0.27) which was accompanied by a reduced myocyte response to β-AR agonist, ISO (10-8 M). In contrast, in ISO-treated β3KO mice (ISO/β3KO), plasma NE (879 pg/ml), EF (62%) and EES (3.6 mmHg/μl) all remained close to control levels with normal ML (124 μm) and H/BW (5.1 g/kg). Importantly, compared with controls, ISO/β3KO myocytes showed no β3-AR expression, but a similar level of β1-AR (0.61), resulting in preserved ISO-stimulated positive inotropic effect with similar increases in dL/dtmax (76% vs 71%) and [Ca2+]iT (33% vs 29%).
Conclusions. Chronic β3-AR deficiency prevents downregulation of LV myocyte β1-ARs and leads to the preservation of myocyte function, [Ca2+]iT, and β-adrenergic responsiveness in a mouse model of progressive HF. Thus, blocking the β3-AR may provide a new strategy for the treatment of HF.
- © 2011 by American Heart Association, Inc.