Abstract 5358: Exacerbated NOS Uncoupling and Adverse Ventricular Remodeling from Pressure-Overload in Mice Lacking Beta3-Adrenoreceptor
Background: Stimulation of the β-adrenergic system plays an important role in the pathological response to sustained cardiac stress, forming the rationale for the use of β-blockers in heart failure. The β3-adrenoreceptor (AR) is thought to couple to the inhibitory G-protein Gi with downstream signaling through nitric oxide, though its role in the heart remains controversial. In this study, we tested whether lack of β3-AR influences the myocardial response to pressure-overload.
Methods: Mice lacking β3-AR (β3−/−, n=25) and wild type (WT, n=25) controls underwent mild transverse aortic constriction (TAC) or sham surgery and were followed for 9 weeks. Cardiac function was measured at baseline and 1, 3 and 9 weeks of TAC by echocardiography. Myocyte width and fibrosis were assessed at 9 weeks. NOS uncoupling was determined by measurement of NOS activity, NOS-dependent superoxide measurement and GTPCH-1 expression.
Results: Baseline cardiac morphology and function by echocardiography were similar in WT and β3−/− mice. β3−/− mice had much greater mortality after TAC than WT controls (p=0.001). By 3 weeks of TAC, left ventricular (LV) wall thickness (1.39±0.07 vs. 1.17±0.04 mm, p<0.05) and mass (252±52 vs.139±8 mg, p<0.05) increased far more in β3−/− hearts than WT, and systolic function was worse. In addition, after 9 weeks of TAC, β3−/−mice had greater LV dilation (3.6±0.25 vs. 2.86±0.04 mm, p<0.01), myocyte hypertrophy (39.29±0.88 μm vs. 31.29±0.86 μm, p<0.001) and enhanced fibrosis (p=0.01). NOS activity declined in β3−/− TAC animals more than in controls (19.3±1.2 vs. 27.7±0.3 cpm/μg protein, p<0.001), and total (2730±121 vs. 1719±52 cpm/mg; p<0.001) and NOS-dependent superoxide (957±184 vs. 422±65 cpm/mg, p<0.05) rose, indicating heightened NOS uncoupling. GTPCH-1 expression was reduced (p<0.001), as was the level of eNOS phosphorylation (p<0.001) in β3−/−-TAC hearts. Myocardial cAMP levels increased in β3−/− TAC vs. WT TAC (p<0.05).
Conclusion: Lack of β3-AR signaling exacerbates cardiac pressure-overload remodeling coupled with enhancing NOS uncoupling and consequent oxidant stress. Selective stimulation of these receptors may provide a novel approach to reducing pathologic hypertrophy in the failing heart
This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).