Abstract 771: Cardiomyocyte-specific Overexpression Of Beta3-adrenoceptors Attenuates The Hypertrophic Response To Catecholamines In Vivo
β1–2 adrenoceptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. We identified the expression of β3 AR in human cardiomyocytes. Their acute activation mediates a negative inotropic effect, but the effect of chronic activation on remodeling is unknown. We analyzed the phenotype of mice with cardiomyocyte-specific (alpha-MHC-driven) expression of human β3 AR (β3-tg). Heterozygote males from a moderately overexpressing line were treated for 2 weeks with 50mg/kg/day isoproterenol (Iso) i.p. or saline. Left ventricular (LV) morphometry was analyzed by echocardiography. Cell dimensions were measured on WGA-stained mid-ventricular heart sections. LV and cell dimensions were comparable between the 2 strains at baseline and after saline. Iso produced LV hypertrophy in WT mice as expected (ΔLV mass/tibial length: +1.01 ± 0.2 vs 0.16± 0.1mg/mm(saline); P=0.002; n=9). Conversely, Iso did not produce a significant hypertrophy in β3-tg mice (0.4± 0.14 vs 0.10± 0.07mg/mm(saline); P=0.078; n=9). Similarly, Iso produced an increase in transverse (139.6±5.8 vs 97.6±5.8 μm2 P<0.0001; n=6) and longitudinal (46.2±1.3 vs 35.6±1.4μm; P<0.0001; n=5) dimensions of cardiomyocytes in WT, but not in β3-tg hearts (Transv: 84.2±3.5 vs 81.0±3.3μm2; P:0.51; Long: 37.1±0.9 vs 35.4±1.1μm; P=0.24; n=6). Chronic Iso did not result in significant impairment of LV function in these mice by echo. RT-qPCR measurements of β AR mRNA abundance revealed a downregulation of β1 -but not β2 AR- mRNA at baseline in β3-tg vs. WT (59.0±5.5% of WT β1 AR, P=0.018 and 128.0±13.0% of WT β2 AR; P=0.17; n=3); although chronic Iso decreased the abundance of β1 AR in WT (50.0±7.8% of saline; P=0.023), it did not further decrease β1-AR in β3-tg mice (83.7±20.5% of saline; P=0.51), resulting in similar β1-AR mRNA levels under Iso in WT and β3-tg ; β2 AR were unchanged by Iso in both strains. In conclusion, cardiac-specific moderate overexpression of β3-AR does not affect cardiac morphology at baseline, but inhibits the hypertrophic response to chronic β-adrenergic stimulation in vivo, despite similar expression levels of β1 and β2 ARs. Activation of the cardiac β3 AR pathway may provide future therapeutic avenues for the modulation of hypertrophic cardiomyopathy.