Abstract 3443: Upregulation of β3-Adrenoceptors (AR) as a Contributing Cause of Reduced Positive Modulation of Adrenergic Signaling in Aged Hearts: Evidence from β3-AR Knockout Mice
Myocardial aging leads to diminished inotropic response to β-adrenergic receptor (AR) stimulation. The molecular mechanism remains unclear. We hypothesize that upregulation of cardiac β3-AR with resultant enhanced negative modulation on β-adrenergic signaling plays a critical role in this age-related event. Thus, aging-induced desensitization of cardiac β3-adrenergic signaling may be attenuated or prevented in β3-AR knockout (β3KO) aged mice. We compared cardiac β3-AR gene expression and myocyte contractile and [Ca2+]i transient ([Ca2+]iT) responses to isoproterenol (ISO, 10−6 to 10−8 M), a non-selective β agonist, and BRL-37,344 (BRL, 10−8 M), a selective β3 agonist, in isolated left ventricular (LV) myocytes obtained from 2 young (Y)(~ 3– 4 mo) and 2 aged (A) (~18 –24 mo) groups (6/group) of wild-type (WT) and β3KO mice, respectively. Compared with YWT myocytes, AWT myocytes showed about 30% decline in basal cell contraction (dL/dtmax, 85.6 vs 122.1 μm/s) and relaxation (dR/dtmax, −61.9 vs −89.9 μm/s) with decreased [Ca2+]iT (0.18 vs 0.21) (p<0.05). There were significantly increased β3-AR mRNA (27%, 0.15±0.01 vs 0.12±0.01) and protein levels accompanied by contrast alterations on myocyte response to β- and β3-AR stimulation. In AWT myocytes, ISO (10−8 M) caused much less increases in dL/dtmax (AWT:30% vs YWT:72%), dR/dtmax (25% vs 56%), and [Ca2+]iT (13% vs 26%); in contrast, BRL produced a much greater decrease in dL/dtmax (17.9% vs 6.9%) and [Ca2+]iT (28.2% vs 18.7%). Compared with YWT, Yβ3KO, which did not alter basal contraction of myocytes, markedly improved the ISO concentration-response curve. Importantly, in contrast to AWT mice, myocytes obtained from Aβ3KO mice showed significantly improved basal cell contraction and relaxation with nearly preserved ISO-stimulated positive inotropic effect. Compared with Yβ3KO, in Aβ3KO mice, ISO caused similar increases in dL/dtmax (78% vs 84%) and [Ca2+]iT (32% vs 34%). Cardiac aging is associated with upregulation of β3-AR, which is a critical determinant to the diminished positive modulation of β-adrenergic signaling, and directly contributes to age-associated deficits in LV myocyte functional performance.
This research has received full or partial funding support from the American Heart Association, AHA National Center.