Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the β3-adrenoreceptor

Stimulation of the beta-adrenergic system is important in the pathological response to sustained cardiac stress, for-ming the rationale for the use of beta-blockers in heart failure. The beta 3-adrenoreceptor (AR) is thought to couple to the inhibitory G-protein, G(1), with downstream signaling through nitric oxide, although its role in the heart remains controversial. In this study, we tested whether lack of beta 3-AR influences the myocardial response to pressure-overload. Baseline echocardiography in mice lacking beta 3-AR (beta 3(-/-)) compared to wild type (WT) showed mild LV hypertrophy at 8 weeks that worsened as they aged. beta 3(-/-) mice had much greater mortality after transverse aortic constriction (TAC) than WT controls. By 3 weeks of TAC. systolic function was worse After 9 weeks of TAC, beta 3(-/-) mice also had greater LV dilation. myocyte hypertrophy and enhanced fibrosis NOS activity declined in beta 3(-/-)TAC hearts after 9 weeks, and total and NOS-dependent superoxide rose, indicating heightened oxidative stress and NOS uncoupling The level of eNOS phosphorylation in beta 3(-/-)TAC hearts was diminished. and nNOS and iNOS expression levels were increased. GTP cyclohydrolase-1 expression was reduced, although total BH4 levels were not depleted. 3 weeks of BH4 treatment rescued beta 3(-/-) mice from worsened remodeling after TAC, and lowered NOS-dependent superoxide. Thus, lack of beta 3-AR signaling exacerbates cardiac pressure-overload induced remodeling and enhances NOS uncoupling and consequent oxidant stress, all of which can be rescued with exogenous BH4. These data suggest a cardioprotective role for the beta 3-AR in modulating oxidative stress and adverse remodeling in the failing heart. (C) 2009 Elsevier Inc. All rights reserved.