Abstract 087: Reversal of Aging-Induced Contrast Changes of Cardiac SERCA 2a and Inducible Nitric Oxide Synthase in Mice Deficient in Beta3-Adrenoreceptor: Insights into the Molecular Mechanism of Cardiac Aging
Background: We have shown previously that aging-induced cardiac dysfunction and β-adrenergic desensitization were prevented in β3-adrenergic receptor (AR) knockout (β3KO) aged mice. However, the molecular mechanism is unclear. We hypothesize that reversal of aging-induced alterations of cardiomyocyte SR Ca2+-ATPase (SERCA 2a) and inducible nitric oxide (NO) synthase by β3-AR deficiency may play a key role for the protective effect.
Methods: We compared SERCA 2a, iNOS, β1- and β3-AR protein expression, myocyte contractile, and [Ca2+]i transient ([Ca2+]iT) responses to isoproterenol (ISO, 10-8 M) in cardiomyocytes obtained from 2 young (Y) (~6 mo) and 2 aged (A) (~26-30 mo) groups (5/group) of wild-type (WT) and β3KO mice, respectively.
Results: Compared with YWT, AWT myocytes had significantly decreased protein levels of SERCA 2a (AWT: 0.22 vs YWT: 0.61) and β1-AR (0.34 vs 0.56), but increased iNOS (0.49 vs 0.24) and β3-AR (0.29 vs 0.14). These changes were associated with reduced basal cell contraction (dL/dtmax) (84.3 vs 124.8 μm/s), relaxation (dR/dtmax) (-66.1 vs -98.8 μm/s), and [Ca2+]iT (0.19 vs 0.23). This was accompanied by diminished ISO-stimulated inotropic response. In AWT myocytes, ISO caused significantly less increases in dL/dtmax (34% vs 82%), dR/dtmax (22% vs 60%), and [Ca2+]iT (15% vs 35%). Compared with YWT, Yβ3KO did not alter basal myocyte contraction and relaxation and response to ISO stimulation, but had significantly increased protein levels of SERCA 2a (Yβ3KO: 1.3 vs YWT: 0.61) and reduced iNOS (0.17 vs 0.24) with relatively unchanged β1-AR (0.63 vs 0.60). Aβ3KO mice had similar alterations. Importantly, in contrast to AWT, in Aβ3KO myocytes, the increased SERCA 2a (1.1) and reduced iNOS (0.19) correlated with normal basal cell contraction and relaxation with preserved ISO-stimulated inotropic response. ISO caused similar increases in dL/dtmax (82% vs 84%) and [Ca2+]iT (31% vs 33%) compared to Yβ3KO mice.
Conclusions: β3-AR deficiency prevents aging-caused downregulation of cardiac β1-ARs and reverses increased iNOS and decreased SERCA 2a, leading to the preservation of myocyte function, [Ca2+]iT, and β-adrenergic reserve in aged hearts. Thus, blocking β3-AR may provide a new strategy for myocardial aging.
- © 2013 by American Heart Association, Inc.