TY - JOUR
T1 - Cardioprotective effect of beta-3 adrenergic receptor agonism
T2 - Role of neuronal nitric oxide synthase
AU - Niu, Xiaolin
AU - Watts, Vabren L.
AU - Cingolani, Oscar H.
AU - Sivakumaran, Vidhya
AU - Leyton-Mange, Jordan S.
AU - Ellis, Carla L.
AU - Miller, Karen L.
AU - Vandegaer, Konrad
AU - Bedja, Djahida
AU - Gabrielson, Kathleen L.
AU - Paolocci, Nazareno
AU - Kass, David A.
AU - Barouch, Lili A.
N1 - Funding Information:
This research was funded by grants from the National Institutes of Health ( K08-HL076220 ), the W.W. Smith Charitable Trust , American Heart Association Beginning Grant-In-Aid, and American Diabetes Association to Dr. Barouch; National Institutes of Health ( 5T32HL007227 ) to Dr. Watts; and the China Scholarship Council to Dr. Niu. Dr. Paolocci has relationships with Cardioxyl Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents to this paper to disclose. Drs. Niu and Watts contributed equally to this work.
PY - 2012/5/29
Y1 - 2012/5/29
N2 - 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.
AB - 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.
KW - heart failure
KW - hypertrophy
KW - nitric oxide synthase
KW - oxidative stress
KW - β3-adrenergic receptor
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U2 - 10.1016/j.jacc.2011.12.046
DO - 10.1016/j.jacc.2011.12.046
M3 - Article
C2 - 22624839
AN - SCOPUS:84861487927
SN - 0735-1097
VL - 59
SP - 1979
EP - 1987
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 22
ER -