Stimulation of the beta-adrenergic system is important in the pathological response
to sustained cardiac stress, forming the rationale for the use of beta-blockers in
heart failure. The beta3-adrenoreceptor (AR) is thought to couple to the inhibitory
G-protein, G(i), with downstream signaling through nitric oxide, although its role
in the heart remains controversial. In this study, we tested whether lack of beta3-AR
influences the myocardial response to pressure-overload. Baseline echocardiography
in mice lacking beta3-AR (beta3(-/-)) compared to wild type (WT) showed mild LV hypertrophy
at 8 weeks that worsened as they aged. beta3(-/-) 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, beta3(-/-) mice also had greater LV dilation,
myocyte hypertrophy and enhanced fibrosis. NOS activity declined in beta3(-/-)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 beta3(-/-)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 beta3(-/-) mice from worsened remodeling after TAC, and lowered
NOS-dependent superoxide. Thus, lack of beta3-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 beta3-AR in modulating oxidative stress and adverse remodeling in the
failing heart.