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

An L. Moens, Jordan S. Leyton-Mange, Xiaolin Niu, Ronghua Yang, Oscar Cingolani, Elisabeth K. Arkenbout, Hunter C. Champion, Djahida Bedja, Kathleen L. Gabrielson, Juan Chen, Yong Xia, Ashley B. Hale, Keith M. Channon, Marc K. Halushka, Norman Barker, Floris L. Wuyts, Pawel M. Kaminski, Michael S. Wolin, David A. Kass, Lili A. Barouch

Research output: Contribution to journalArticlepeer-review

Abstract

Stimulation of the β-adrenergic system is important in the pathological response to sustained cardiac stress, forming the rationale for the use of β-blockers in heart failure. The β3-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 β3-AR influences the myocardial response to pressure-overload. Baseline echocardiography in mice lacking β3-AR (β3-/-) compared to wild type (WT) showed mild LV hypertrophy at 8 weeks that worsened as they aged. β3-/- 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, β3-/- mice also had greater LV dilation, myocyte hypertrophy and enhanced fibrosis. NOS activity declined in β3-/-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 β3-/-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 β3-/- mice from worsened remodeling after TAC, and lowered NOS-dependent superoxide. Thus, lack of β3-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 β3-AR in modulating oxidative stress and adverse remodeling in the failing heart.

Original languageEnglish (US)
Pages (from-to)576-585
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume47
Issue number5
DOIs
StatePublished - Nov 1 2009

Keywords

  • Hypertrophy
  • NOS uncoupling
  • Oxidative stress
  • Pressure-overload
  • Tetrahydrobiopterin
  • β3-adrenoreceptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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