Abstract 14261: Molecular Basis of the Protective Effect of β3-Adrenergic Receptor Deficiency on Myocardial Aging: Reversal of Aging-Induced Contrast Changes of Cardiac SERCA 2a and Inducible Nitric Oxide Synthase
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 cardiac SR Ca2+-ATPase (SERCA2a) and inducible nitric oxide synthase (iNOS) by β3KO may play a key role for the protective effect.
Methods: We compared protein levels of β1- and β3-AR, SERCA2a and iNOS, myocyte contractile, [Ca2+]i transient ([Ca2+]iT) and Ca current (ICa,L) responses to isoproterenol (ISO, 10-8 M) in LV myocytes obtained from 2 young (Y) (~6 m) and 2 aged (A) (~28 m) groups (6/group) of wild-type (WT) and β3KO mice, respectively.
Results: Compared with YWT, AWT myocytes had significantly decreased protein levels of SERCA2a (AWT: 0.23 vs YWT: 0.64), and β1-AR (0.33 vs 0.58), but increased iNOS (0.50 vs 0.23) and β3-AR (0.34 vs 0.15) with reduced basal cell contraction (dL/dtmax) (84.5 vs 126.4 μm/s), relaxation (dR/dtmax) (66.9 vs 101.8 μm/s), [Ca2+]iT (0.18 vs 0.24), and ICa,L(4.4 vs 7.7 pA/pF). These changes were accompanied by diminished ISO-stimulated inotropic response. In AWT myocytes, ISO caused significantly less increases in dL/dtmax (AWT: 33% vs YWT: 80%), dR/dtmax (24% vs 62%), [Ca2+]iT(16% vs 37%) and ICa,L (15% vs 33%). Versus YWT, Yβ3KO did not alter basal myocyte contraction and relaxation and response to ISO stimulation, but had significantly increased protein levels of SERCA2a (Yβ3KO: 1.40 vs YWT: 0.62) and reduced iNOS (0.18 vs 0.26) with unchanged β1-AR (0.65 vs 0.62). Aβ3KO mice had similar alterations. Importantly, in contrast to AWT, in Aβ3KO myocytes, the increased SERCA2a (1.2) and reduced iNOS (0.16) correlated with normal basal cell contraction and relaxation with preserved ISO-stimulated inotropic response. ISO caused similar increases in dL/dtmax (Aβ3KO: 80% vs Yβ3KO: 83%), dR/dtmax (68% vs 61%), [Ca2+]iT (30% vs 32%) and ICa,L (29% vs 31%).
Conclusions: β3KO prevents aging-caused downregulation of cardiac β1-ARs and reverses increased iNOS and decreased SERCA2a, leading to the preservation of myocyte function, [Ca2+]iT, ICa,L and β-adrenergic reserve in aged hearts. Thus, β3-AR may provide a new target for cardiac aging.
Author Disclosures: H. Cheng: None. P. Zhou: None. T. Li: None. X. Zhang: None. S. Masutani: None. D. Kitzman: None. W. Little: None. C. Cheng: None.
- © 2015 by American Heart Association, Inc.