Background-Silent information regulator 1 (Sirt1), a class III histone deacetylase, retards aging and protects the heart from oxidative stress. We here examined whether Sirt1 is protective against myocardial ischemia/reperfusion (I/R). Methods and Results-Protein and mRNA expression of Sirt1 is significantly reduced by I/R. Cardiac-specific Sirt1 Ϫ/Ϫ mice exhibited a significant increase (44Ϯ5% versus 15Ϯ5%; Pϭ0.01) in the size of myocardial infarction/area at risk. In transgenic mice with cardiac-specific overexpression of Sirt1, both myocardial infarction/area at risk (15Ϯ4% versus 36Ϯ8%; Pϭ0.004) and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei (4Ϯ3% versus 10Ϯ1%; PϽ0.003) were significantly reduced compared with nontransgenic mice. In Langendorff-perfused hearts, the functional recovery during reperfusion was significantly greater in transgenic mice with cardiac-specific overexpression of Sirt1 than in nontransgenic mice. Sirt1 positively regulates expression of prosurvival molecules, including manganese superoxide dismutase, thioredoxin-1, and Bcl-xL, whereas it negatively regulates the proapoptotic molecules Bax and cleaved caspase-3. The level of oxidative stress after I/R, as evaluated by anti-8-hydroxydeoxyguanosine staining, was negatively regulated by Sirt1. Sirt1 stimulates the transcriptional activity of FoxO1, which in turn plays an essential role in mediating Sirt1-induced upregulation of manganese superoxide dismutase and suppression of oxidative stress in cardiac myocytes. Sirt1 plays an important role in mediating I/R-induced increases in the nuclear localization of FoxO1 in vivo. Conclusions-These results suggest that Sirt1 protects the heart from I/R injury through upregulation of antioxidants and downregulation of proapoptotic molecules through activation of FoxO and decreases in oxidative stress. (Circulation. 2010;122:2170-2182.)Key Words: cardioprotection Ⅲ ischemia Ⅲ oxidative stress Ⅲ reperfusion injury S ilent information regulator 1 (Sirt1) is a member of the sirtuin family of class III histone deacetylases. 1 The class III histone deacetylases are distinguished from histone deacetylases in the other classes by their requirement of NAD ϩ for their enzyme activity. 2 Sirt1 is involved in gene silencing, differentiation, cell survival, metabolism, and longevity. 1 Sirt1 activity extends the lifespan of lower organisms, including yeast, Caenorhabditis elegans, and flies. 3,4 In addition, resveratrol, which stimulates Sirt1, extends the lifespan of mice fed a high-fat diet, suggesting that Sirt1 may affect aging and/or lifespan in mammals. 5 The beneficial effects of caloric restriction may be dependent on Sirt1. 6 -8 Conversely, Sirt1 knockout mice exhibit developmental abnormalities, including septal and valvular heart defects. 9,10 Sirt1 regulates the function of transcription factors and cofactors, including MyoD, Ku, p53, PGC1, and the FoxO family of transcription factors, 11-19 through deacetylation. Clinical Perspective on p 2182Activation of mole...

Rationale: NAD؉ acts not only as a cofactor for cellular respiration but also as a substrate for NAD ؉ -dependent enzymes, such as Sirt1. The cellular NAD ؉ synthesis is regulated by both the de novo and the salvage pathways. Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the salvage pathway. Objective: Here we investigated the role of Nampt in mediating NAD ؉ synthesis in cardiac myocytes and the function of Nampt in the heart in vivo. Methods and Results: Expression of Nampt in the heart was significantly decreased by ischemia, ischemia/ reperfusion and pressure overload. Upregulation of Nampt significantly increased NAD ؉ and ATP concentrations, whereas downregulation of Nampt significantly decreased them. Downregulation of Nampt increased caspase 3 cleavage, cytochrome c release, and TUNEL-positive cells, which were inhibited in the presence of Bcl-xL, but did not increase hairpin 2-positive cells, suggesting that endogenous Nampt negatively regulates apoptosis but not necrosis. Downregulation of Nampt also impaired autophagic flux, suggesting that endogenous Nampt positively regulates autophagy. Cardiac-specific overexpression of Nampt in transgenic mice increased NAD ؉ content in the heart, prevented downregulation of Nampt, and reduced the size of myocardial infarction and apoptosis in response to prolonged ischemia and ischemia/reperfusion. Conclusions: Nampt critically regulates NAD ؉ and ATP contents, thereby playing an essential role in mediating cell survival by inhibiting apoptosis and stimulating autophagic flux in cardiac myocytes. Preventing downregulation of Nampt inhibits myocardial injury in response to myocardial ischemia and reperfusion. These results suggest that Nampt is an essential gatekeeper of energy status and survival in cardiac myocytes. Because of its involvement in the mitochondrial TCA cycle and the electron transport chain, NAD ϩ acts as a key cofactor for energy production. NAD ϩ also serves as the substrate for various enzymes, including the nuclear enzyme poly(ADPribose) polymerase (PARP)-1, 1 and the class III histone deacetylases, ie, the sirtuin family. 2 Because the sirtuin family plays an essential role in mediating lifespan extension, stress resistance and regulation of metabolism, 3 NAD ϩ may control the level of stress resistance in cells partly through regulation of sirtuins. 4 NAD ϩ can be freshly synthesized from amino acids, including tryptophan or aspartic acid, via the de novo pathway 5 or taken up efficiently from the extracellular space. 6 Importantly, NAD ϩ can also be resynthesized from NAD ϩ metabolites through the salvage pathway. 5 In yeast, increased expression of pyrazinamidase/nicotinamidase 1, a nicotinamidase converting nicotinamide to nicotinic acid, is both necessary and sufficient for lifespan extension induced by calorie restriction and low-intensity stress, such as osmotic stress. 7 Nicotinamide phosphoribosyltransferase (Nampt) is a ratelimiting enzyme in the mammalian NAD ϩ salvage pathway, and has been prop...

Summary 5'-AMP-activated protein kinase (AMPK) is a key regulator of metabolism and survival during energy stress. Dysregulation of AMPK is strongly associated with oxidative stress-related disease. However, whether and how AMPK is regulated by intracellular redox status remains unknown. Here we show that the activity of AMPK is negatively regulated by oxidation of Cys130 and Cys174 in its a subunit, which interferes with the interaction between AMPK and AMPK kinases (AMPKK). Reduction of Cys130/Cys174 is essential for activation of AMPK during energy starvation. Thioredoxin1 (Trx1), an important reducing enzyme that cleaves disulfides in proteins, prevents AMPK oxidation, serving as an essential cofactor for AMPK activation. High-fat diet consumption downregulates Trx1 and induces AMPK oxidation, which enhances cardiomyocyte death during myocardial ischemia. Thus, Trx1 modulates activation of the cardioprotective AMPK pathway during ischemia, functionally linking oxidative stress and metabolism in the heart.

What prompted you to investigate this topic? The increasing worldwide availability of naturala nd shale gas has stimulated aq uick technical shift to catalytic dehydrogena-tion of propane to propylene (PDH). However,t his technology relies on Pt-or CrO x-basedc atalysts and suffers from thermo-dynamic limitations and rapid catalystd eactivation by coking and sintering. Oxidative dehydrogenation (ODH) of propane offers ap romising alternative to industrialized PDH process, but selectivity control foro lefins is difficult, because of deep-oxidation reactions over conventional metal oxide catalysts that produce as ubstantial amount of undesired CO 2 .H ence, we have dedicated our efforts to the development of at her-mally stable and metal-free ODH catalyst, which can selectively cleave the CÀHb ond while preventing CO 2 formation. As presented in this paper,e dge-hydroxylated boron nitride addresses these issues. What new scientific questions/problems doest his work raise? This work represents af undamental breakthrough in chemistry because non-metallic, inert boron nitride was transformed into ac hemically active and selectivec atalystf or propaneO DH. We have identified the BÀOH groups at the edges of BN as active sites forp ropane ODH. However, aw ell-defined reaction pathway remainsu nclear.F uture studies should focus on theoretical simulations and the captureo fr eaction intermediates to illustrate the reactionm echanism under real reaction conditions.