Abstract 13008: Reversal of Aging-Induced Upregulation of Cardiac Inducible Nitric Oxide Synthase and Beta-Adrenergic Desensitization in Mice Lacking the Beta3-Adrenoreceptor
Background: We have shown previously that cardiac aging (CA) is associated with enhanced β3-adrenergic receptor (AR)-evoked inhibition of cardiomyocyte function accompanied by hyporesponsiveness to β3-AR stimulation. We hypothesize that upregulation of β3-AR-mediated inducible nitric oxide synthase (iNOS)/NO-coupled pathway may play a critical role in this age-related event. Chronic β3-AR deficiency may reverse these CA-caused changes and play a protective effect.
Methods: We compared iNOS and β1- and β3-AR protein expression, myocyte contractile, and [Ca2+]i transient ([Ca2+]iT) responses to isoproterenol (ISO, 10-8M) in left ventricle (LV) myocytes obtained from 2 young (Y) (∼6 mo) and 2 aged (A) (∼24 mo) groups (5/group) of wild-type (WT) and β3KO mice, respectively.
Results: Compared with YWT, AWT myocytes had significant increases in iNOS (0.49 vs 0.24), plasma levels of NOX (119.8 vs 40.6 mmol/L) and β3-AR (0.27 vs 0.14), but decreased β1-AR (0.41 vs 0.60). These changes were associated with reduced basal cell contraction (dL/dtmax) (82.6 vs 121.9 μm/s), relaxation (dR/dtmax) (-60.9 vs -90.2 μm/s), and [Ca2+]iT (0.16 vs 0.23) accompanied by diminished ISO-stimulated inotropic response. In AWT myocytes, ISO (10-8M) caused significantly less increases in dL/dtmax (34% vs 83%), dR/dtmax(25% vs 59%), and [Ca2+]iT (15% vs 36%). Compared with YWT, Yβ3KO had significantly reduced iNOS (0.17 vs 0.24) with relatively unchanged NOX (39.6 mmol/L), basal myocyte contraction and ISO responses. Importantly, in contrast to AWT, in Aβ3KO myocytes, there were significantly reduced iNOS (0.19) and NOX (38.4 mmol/L), but increased β1-AR (0.63). These changes correlated with normal basal cell contraction and relaxation with preserved ISO-stimulated positive inotropic response. ISO caused similar increases in dL/dtmax (86% vs 83%) and [Ca2+]iT (34% vs 37%) compared to Yβ3KO mice.
Conclusions: Chronic β3-AR deficiency reverses β3-AR-activated upregulation of cardiac iNOS, prevents aging-induced downregulation of β1-ARs, and leads to the preservation of myocyte function, [Ca2+]iT, and β-adrenergic responsiveness in aged hearts. Thus, antagonizing β3-AR could be a new therapeutic strategy for age-related decline in myocardial function.
- © 2010 by American Heart Association, Inc.