title: Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xinsi Road, Xi'an, China. nx1810120@hotmail.com [corrected].
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Niu
authors.forename: Vabren L
authors.initials: VL
authors.lastname: Watts
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Cingolani
authors.forename: Vidhya
authors.initials: V
authors.lastname: Sivakumaran
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Leyton-Mange
authors.forename: Carla L
authors.initials: CL
authors.lastname: Ellis
authors.forename: Karen L
authors.initials: KL
authors.lastname: Miller
authors.forename: Konrad
authors.initials: K
authors.lastname: Vandegaer
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Lili A
authors.initials: LA
authors.lastname: Barouch
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002395:Catecholamines / Q000097:blood; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D002395:Catecholamines; D017382:Reactive Oxygen Species; D013481:Superoxides; D052248:Nitric Oxide Synthase Type I