Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway.
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.
Pillai
Vinodkumar B
VB
Department of Surgery, University of Chicago, Chicago, Illinois 60637, USA.
Sundaresan
Nagalingam R
NR
Kim
Gene
G
Gupta
Madhu
M
Rajamohan
Senthilkumar B
SB
Pillai
Jyothish B
JB
Samant
Sadhana
S
Ravindra
P V
PV
Isbatan
Ayman
A
Gupta
Mahesh P
MP
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000473:pathology; D006333:Heart Failure; D006984:Hypertrophy; D051379:Mice; D008822:Mice, Transgenic; D009243:NAD / Q000737:chemistry*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species; D056566:Sirtuin 3 / Q000378:metabolism*
D017382:Reactive Oxygen Species; C525046:Sirt3 protein, mouse; D009243:NAD; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D056566:Sirtuin 3