Abstract 9703: Cardiac β 3 -Adrenergic Receptor Deficiency Mice Protected from Cardiac Aging: Insights into the Cellular and Molecular Mechanism of Myocardial Aging

Abstract

Background: We have shown previously that aging-caused declines in cardiac function and β-adrenergic reserve were prevented in β 3 -adrenergic receptor (AR) knockout (β 3 KO) aged mice. The cellular and molecular mechanisms are unclear. We hypothesize that reversal of aging-induced downregulations of cardiac SR Ca 2+ -ATPase (SERCA2a) and β 1 -AR may lead to normalization of myocyte [Ca 2+ ] i regulation, β-AR regulation, and preserving normal myocyte function, thereby preventing aging-induced cardiac dysfunction and eliminating myocardial aging. Methods: We compared protein levels of β 1 - and β 3 -AR, and SERCA2a, myocyte contractile, [Ca 2+ ] i transient ([Ca 2+ ] iT ) and calcium current (I Ca,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 (7/group) of wild-type (WT) and β 3 KO mice, respectively. Results: Compared with YWT, AWT myocytes had significantly decreased protein levels of SERCA2a (AWT: 0.24 vs YWT: 0.67), and β 1 -AR (0.35 vs 0.59), but increased β 3 -AR (0.36 vs 0.16) with reduced basal cell contraction (dL/dt max ) (85.3 vs 126.8μm/s), relaxation (dR/dt max ) (66.7 vs 102.1 μm/s), [Ca 2+ ] iT (0.18 vs 0.24), and I Ca,L (4.3 vs 7.6 pA/pF). These changes were accompanied by diminished ISO-stimulated inotropic response. In AWT myocytes, ISO caused significantly less increases in dL/dt max (34% vs 82%), dR/dt max (26% vs 64%), [Ca 2+ ] iT (16% vs 38%) and I Ca,L (15% vs 34%). Versus YWT, Yβ 3 KO did not alter basal myocyte contraction and relaxation and response to ISO stimulation, but had significantly increased protein levels of SERCA2a (1.41 vs 0.61) and unchanged β 1 -AR (0.65 vs 0.62). Aβ 3 KO mice had similar alterations. Importantly, in contrast to AWT, in Aβ 3 KO myocytes, there was increased SERCA2a (1.3) associated with normal basal cell contraction and relaxation, and preserved ISO-stimulated inotropic response. ISO caused similar increases in dL/dt max (Aβ 3 KO: 81% vs Yβ 3 KO: 83%), dR/dt max (68% vs 62%), [Ca 2+ ] iT (31% vs 32%) and I Ca,L (30% vs 32%). Conclusions: β 3 KO prevents aging-caused downregulations of cardiac β 1 -ARs and SERCA2a, leading to the preservation of myocyte function, [Ca 2+ ] iT , I Ca,L and β-adrenergic reserve in aged hearts. Thus, β 3 -AR may provide a new target for cardiac aging.