Cardioprotective Effect of Beta-3 Adrenergic Receptor Agonism
| Autor: | Vidhya Sivakumaran, Oscar H. Cingolani, Konrad Vandegaer, Karen L. Miller, Carla LaShannon Ellis, Djahida Bedja, Lili A. Barouch, Nazareno Paolocci, Vabren L. Watts, David A. Kass, Jordan S Leyton-Mange, Kathleen L. Gabrielson, Xiaolin Niu |
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| Rok vydání: | 2012 |
| Předmět: |
Pressure overload
chemistry.chemical_classification medicine.medical_specialty Reactive oxygen species biology business.industry medicine.disease biology.organism_classification Endothelial NOS Muscle hypertrophy Nitric oxide Nitric oxide synthase chemistry.chemical_compound Endocrinology chemistry Enos Internal medicine medicine biology.protein Cardiology and Cardiovascular Medicine Ventricular remodeling business |
| Zdroj: | Journal of the American College of Cardiology. 59:1979-1987 |
| ISSN: | 0735-1097 |
| DOI: | 10.1016/j.jacc.2011.12.046 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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