Publication
Title
Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the -adrenoreceptor
Author
Abstract
Stimulation of the â-adrenergic system is important in the pathological response to sustained cardiac stress, forming the rationale for the use of â-blockers in heart failure. The â3-adrenoreceptor (AR) is thought to couple to the inhibitory G-protein, Gi, with downstream signaling through nitric oxide, although its role in the heart remains controversial. In this study, we tested whether lack of â3-AR influences the myocardial response to pressure-overload. Baseline echocardiography in mice lacking â3-AR (â3−/−) compared to wild type (WT) showed mild LV hypertrophy at 8 weeks that worsened as they aged. â3−/− 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, â3−/− mice also had greater LV dilation, myocyte hypertrophy and enhanced fibrosis. NOS activity declined in â3−/−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 â3−/−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 â3−/− mice from worsened remodeling after TAC, and lowered NOS-dependent superoxide. Thus, lack of â3-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 â3-AR in modulating oxidative stress and adverse remodeling in the failing heart.
Language
English
Source (journal)
Journal of molecular and cellular cardiology. - London
Publication
London : 2009
ISSN
0022-2828
Volume/pages
47:5(2009), p. 576-585
ISI
000271108000004
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 26.01.2010
Last edited 03.08.2017
To cite this reference