Exogenous NAD Blocks Cardiac Hypertrophic Response via Activation of the SIRT3-LKB1-AMP-activated Kinase Pathway

Abstract

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 exerciseinduced 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.Cardiac hypertrophy is a complex growth response of the heart, whereby terminally differentiated cardiac myocytes structurally, genetically, and functionally remodel in response to a variety of physiologic and pathologic stimuli. In settings of pathologic stimuli, such as hypertension, ischemic disease, or valvular insufficiency, cardiac hypertrophy develops with enlarged cardiomyocytes, which are associated with formation of new sarcomeres and induction of a group of genes (fetal genes), which are usually expressed during development of the fetal heart. These changes provide a short term mechanism for decreasing ventricular wall stress and improving heart function. However, during prolonged intervals of pathologic hypertrophy, this program becomes maladaptive, resulting in myocyte cell death, fibrosis, and ventricular dilation and the transition to heart failure (1). Recent evidence suggests that reduction of cardiac hypertrophy could block the onset of heart failure and improve patient survival (1-3). One novel approach that is gaining increasing attention in this direction is the activation of endogenous cell signaling pathways that negatively regulate cardiac hypertrophy (4). Exogenous agents that can facilitate the activity of these pathways are of particular interest as new therapeutic tools for the management of cardiac hypertrophy and heart failure.At the cellular level various signaling mechanisms have been described that lead to development of cardiac hypertrophy. Among them, oxidative stress is recognized as a critical common signal to various stimuli, which directs to evolution of pathologic hypertrophy (5). Severe oxidative stress can result in increased NAD turnover due to increased activity of NAD-consuming enzymes such as poly(ADP-ribose) polymerase-1 and/or decreased activity...

Hypertrophic and Inflammatory Markers in Isoproterenol-Induced CardiacHypertrophy and its Pharmacological Correction

“…Treatment with exogenous NAD blocked the induction of atrial natriuretic factor release from nuclei, thus suggesting the antihypertrophic activity of NAD [6]. The results indicated that phenylephrine (PE, 20 µM)-mediated activation of these promoters was significantly reduced by treatment of cells with NAD, thus again demonstrating the anti-hypertrophic potential of NAD [6,19,20]. Early, Sukoyan has shown that treatment with oxidized form of NAD (preparation of Nadcin  ) reversed ischemic-reperfusion injury of myocardium in experimental models [16][17][18] and Bokeria confirm these results in randomized controlled study in patients with unstable angina pectoris and bypass grafting [21].…”

trans-(−)-ε-Viniferin Increases Mitochondrial Sirtuin 3 (SIRT3), Activates AMP-activated Protein Kinase (AMPK), and Protects Cells in Models of Huntington Disease

“…Recent evidence has shown that SIRT3 is involved in mitochondrial energy metabolism and biogenesis (56) and preservation of ATP biosynthetic capacity in the heart (45). SIRT3 knock-out resulted in a marked decrease in basal ATP in vivo (57) and eliminated the role of SIRT3 in protection of cells from oxidative stress (58). Our study suggests that viniferin increases SIRT3, stimulates AMPK activities, and preserves NAD levels, and therefore, could have a pivotal role in protecting neurons from mutant Htt, which promotes bioenergetic failure.…”

From Sirtuin Biology to Human Diseases: An Update

“…Sirt3-deficient mice develop cardiac hypertrophy, whereas transgenic animals overexpressing SIRT3 in the heart are protected against agonist-mediated cardiac hypertrophy (84). At the molecular level, SIRT3 deacetylates and activates LKB1, thereby activating AMP-activated kinase, which suppresses Akt phosphorylation (85). Moreover, SIRT3-dependent deacetylation of FoxO3a leads to its nuclear localization and enhanced expression of antioxidant genes, such as manganese superoxide dismutase, reducing cellular ROS levels (84).…”