title: Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor.
abstract: 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.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: An L
authors.initials: AL
authors.lastname: Moens
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Leyton-Mange
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Niu
authors.forename: Ronghua
authors.initials: R
authors.lastname: Yang
authors.forename: Oscar
authors.initials: O
authors.lastname: Cingolani
authors.forename: Elisabeth K
authors.initials: EK
authors.lastname: Arkenbout
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Hale
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.forename: Norman
authors.initials: N
authors.lastname: Barker
authors.forename: Floris L
authors.initials: FL
authors.lastname: Wuyts
authors.forename: Pawel M
authors.initials: PM
authors.lastname: Kaminski
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Lili A
authors.initials: LA
authors.lastname: Barouch
mesh_terms: 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*
chemical_list: D022702:Receptors, Adrenergic, beta-3; D013481:Superoxides; D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin