Exogenous NAD Blocks Cardiac Hypertrophic Response via Activation of the SIRT3-LKB1-AMP-activated Kinase Pathway
| Autor: | P. V. Ravindra, Nagalingam R. Sundaresan, Jyothish B. Pillai, Sadhana Samant, Madhu Gupta, Gene Kim, Mahesh P. Gupta, Ayman Isbatan, Senthilkumar B. Rajamohan, Vinodkumar B. Pillai |
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| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
SIRT3 Transgene Cardiomegaly Mice Transgenic AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Biochemistry Muscle hypertrophy Mice AMP-Activated Protein Kinase Kinases AMP-activated protein kinase Sirtuin 3 Internal medicine medicine Animals Molecular Biology Heart Failure biology Mechanisms of Signal Transduction Hypertrophy Cell Biology NAD Rats Cell biology Endocrinology biology.protein NAD+ kinase Histone deacetylase Signal transduction Reactive Oxygen Species Intracellular Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 285:3133-3144 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m109.077271 |
| Popis: | Since the discovery of NAD-dependent deacetylases, sirtuins, it has been recognized that maintaining intracellular levels of NAD is crucial for the management of stress response of cells. Here we show that agonist-induced cardiac hypertrophy is associated with loss of intracellular levels of NAD, but not exercise-induced physiologic hypertrophy. Exogenous addition of NAD was capable of maintaining intracellular levels of NAD and blocking the agonist-induced cardiac hypertrophic response in vitro as well as in vivo. NAD treatment blocked the activation of pro-hypertrophic Akt1 signaling, and augmented the activity of anti-hypertrophic LKB1-AMPK signaling in the heart, which prevented subsequent induction of mTOR-mediated protein synthesis. By using gene knock-out and transgenic mouse models of SIRT3 and SIRT1, we showed that the anti-hypertrophic effects of exogenous NAD are mediated through activation of SIRT3, but not SIRT1. SIRT3 deacetylates and activates LKB1, thus augmenting the activity of the LKB1-AMPK pathway. These results reveal a novel role of NAD as an inhibitor of cardiac hypertrophic signaling, and suggest that prevention of NAD depletion may be critical in the treatment of cardiac hypertrophy and heart failure. |
| Databáze: | OpenAIRE |
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