Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor.
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.
Moens
An L
AL
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Leyton-Mange
Jordan S
JS
Niu
Xiaolin
X
Yang
Ronghua
R
Cingolani
Oscar
O
Arkenbout
Elisabeth K
EK
Champion
Hunter C
HC
Bedja
Djahida
D
Gabrielson
Kathleen L
KL
Chen
Juan
J
Xia
Yong
Y
Hale
Ashley B
AB
Channon
Keith M
KM
Halushka
Marc K
MK
Barker
Norman
N
Wuyts
Floris L
FL
Kaminski
Pawel M
PM
Wolin
Michael S
MS
Kass
David A
DA
Barouch
Lili A
LA
D000367:Age Factors; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000627:therapeutic use; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D004452:Echocardiography; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*
D022702:Receptors, Adrenergic, beta-3; D013481:Superoxides; D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin