- 作者：Xiaolin Niu ; MD ; PhD鈦?/sup> ; &dagger ; ; nx180120@hotmail.com ; Vabren L. Watts ; PhD&dagger ; ; Oscar H. Cingolani ; MD&dagger ; ; Vidhya Sivakumaran ; PhD&dagger ; ; Jordan S. Leyton-Mange ; MD&dagger ; ; Carla L. Ellis ; MD§ ; ; Karen L. Miller&dagger ; ; Konrad Vandegaer ; BS&dagger ; ; Djahida Bedja ; MS&Dagger ; ; Kathleen L. Gabrielson ; DVM ; PhD&Dagger ; ; Nazareno Paolocci ; MD&dagger ; ; David A. Kass ; MD&dagger ; ; Lili A. Barouch ; MD&dagger ; ; barouch@jhmi.edu
- 关键词：尾3-adrenergic receptor ; heart failure ; hypertrophy ; nitric oxide synthase ; oxidative stress
- 刊名：Journal of the American College of Cardiology
- 出版年：2012
- 期刊代码：201_07351097
- 类别：med
- 出版时间：29 May, 2012
- 卷：59
- 期：22
- 页码：1979-1987
- 文件大小：890 K
Objectives
The aim of this study was to determine whether activation of 尾3-adrenergic receptor (AR) and downstream signaling of nitric oxide synthase (NOS) isoforms protects the heart from failure and hypertrophy induced by pressure overload.Background
尾3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike 尾1- and 尾2-ARs, 尾3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a 鈥渂rake鈥?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 (尾3 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 尾3-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.