Document Detail

Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase.
MedLine Citation:
PMID:  22624839     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: The aim of this study was to determine whether activation of β3-adrenergic receptor (AR) and downstream signaling of nitric oxide synthase (NOS) isoforms protects the heart from failure and hypertrophy induced by pressure overload.
BACKGROUND: β3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike β1- and β2-ARs, β3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a "brake" to protect the heart from catecholamine overstimulation.
METHODS: C57BL/6J and neuronal NOS (nNOS) knockout mice were assigned to receive transverse aortic constriction (TAC), BRL37344 (β3 agonist, BRL 0.1 mg/kg/h), or both.
RESULTS: Three weeks of BRL treatment in wild-type mice attenuated left ventricular dilation and systolic dysfunction, and partially reduced cardiac hypertrophy induced by TAC. This effect was associated with increased nitric oxide production and superoxide suppression. TAC decreased endothelial NOS (eNOS) dimerization, indicating eNOS uncoupling, which was not reversed by BRL treatment. However, nNOS protein expression was up-regulated 2-fold by BRL, and the suppressive effect of BRL on superoxide generation was abrogated by acute nNOS inhibition. Furthermore, BRL cardioprotective effects were actually detrimental in nNOS(-/-) mice.
CONCLUSIONS: These results are the first to show in vivo cardioprotective effects of β3-AR-specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as the primary downstream NOS isoform in maintaining NO and reactive oxygen species balance in the failing heart.
Xiaolin Niu; Vabren L Watts; Oscar H Cingolani; Vidhya Sivakumaran; Jordan S Leyton-Mange; Carla L Ellis; Karen L Miller; Konrad Vandegaer; Djahida Bedja; Kathleen L Gabrielson; Nazareno Paolocci; David A Kass; Lili A Barouch
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  59     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-25     Completed Date:  2012-07-31     Revised Date:  2013-06-24    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1979-87     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xinsi Road, Xi'an, China. [corrected].
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MeSH Terms
Adrenergic beta-3 Receptor Agonists / pharmacology*
Blotting, Western
Catecholamines / blood
Disease Models, Animal
Follow-Up Studies
Heart Failure / blood,  physiopathology,  prevention & control*
Hypertrophy, Left Ventricular / blood,  physiopathology,  prevention & control*
Magnetic Resonance Spectroscopy
Mice, Inbred C57BL
Mice, Knockout
Myocardial Contraction / drug effects*
Myocardium / enzymology*,  pathology
Nitric Oxide Synthase Type I / biosynthesis*
Oxidative Stress / drug effects
Reactive Oxygen Species / metabolism
Superoxides / metabolism
Ventricular Remodeling / drug effects,  physiology*
Grant Support
Reg. No./Substance:
0/Adrenergic beta-3 Receptor Agonists; 0/Catecholamines; 0/Reactive Oxygen Species; 11062-77-4/Superoxides; EC Oxide Synthase Type I
Comment In:
J Am Coll Cardiol. 2012 May 29;59(22):1988-90   [PMID:  22624840 ]
Erratum In:
J Am Coll Cardiol. 2012 Jul 31;60(5):481

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