Silent Information Regulator 1 Protects the Heart From Ischemia/Reperfusion

Abstract

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...

SIRT1 modulates MAPK pathways in ischemic–reperfused cardiomyocytes

“…It was shown that Resv protects H9c2 cells from hypoxia-induced apoptosis by signaling via the SIRT1-FOXO1 pathway [15]. Moreover, SIRT1-induced upregulation of antioxidants and downregulation of pro-apoptotic molecules, via FOXO activation and reduction of oxidative stress, protecting transgenic mice from IR-induced cardiac injury [30].…”

“…A recent study by Hsu and colleagues found that SIRT1 upregulates the expression of cardioprotective molecules, such as MnSOD, Trx1, and Bcl-xL, and at the same time downregulates pro-apoptotic molecules, including Bax [30]. SIRT1 is also known to deacetylate FOXO, leading to upregulated expression of genes involved in cell-protective processes [34].…”

Redox Signaling Pathways Involved in Neuronal Ischemic Preconditioning

“…Similarly, IPC increased SIRT1 enzymatic activity and neuroprotection in an in vivo rat model of cardiac arrest [114]. SIRT1 is also activated in the heart following IPC and provides cardioprotection from ischemia and coronary artery occlusion [115][116][117].…”

Redox-regulating sirtuins in aging, caloric restriction, and exercise

“…Therefore, it seems that oxidants could affect sirtuins via depletion of NAD þ and oxidative modification of amino acid residues, leading to decreased activity or level of the enzyme [40,44]. On the other hand, it has also been shown that the overexpression of SIRT1 has beneficial effects in resistance to oxidative stress [39,44,45].…”