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...
Background Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood. Methods and Results Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure (HF) was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Mito-Keima, was transiently activated around 3–7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and HF after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on Day 7 after TAC partially rescued mitochondrial autophagy, and attenuated mitochondrial dysfunction and HF induced by pressure overload (PO). Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. Conclusions Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to PO. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and HF, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during PO.
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...
Increasing evidence suggests that PRMT5, a protein arginine methyltransferase, is involved in tumorigenesis. However, no systematic research has demonstrated the cell‐transforming activity of PRMT5. We investigated the involvement of PRMT5 in tumor formation. First, we showed that PRMT5 was associated with many human cancers, through statistical analysis of microarray data in the NCBI GEO database. Overexpression of ectopic PRMT5 per se or its specific shRNA enhanced or reduced cell growth under conditions of normal or low concentrations of serum, low cell density, and poor cell attachment. A stable clone that expressed exogenous PRMT5 formed tumors in nude mice, which demonstrated that PRMT5 is a potential oncoprotein. PRMT5 accelerated cell cycle progression through G1 phase and modulated regulators of G1; for example, it upregulated cyclin‐dependent kinase (CDK) 4, CDK6, and cyclins D1, D2 and E1, and inactivated retinoblastoma protein (Rb). Moreover, PRMT5 activated phosphoinositide 3‐kinase (PI3K)/AKT and suppressed c‐Jun N‐terminal kinase (JNK)/c‐Jun signaling cascades. However, only inhibition of PI3K activity, and not overexpression of JNK, blocked PRMT5‐induced cell proliferation. Further analysis of PRMT5 expression in 64 samples of human lung cancer tissues by microarray and western blot analysis revealed a tight association of PRMT5 with lung cancer. Knockdown of PRMT5 retarded cell growth of lung cancer cell lines A549 and H1299. In conclusion, to the best of our knowledge, we have characterized the cell‐transforming activity of PRMT5 and delineated its underlying mechanisms for the first time.
Autophagy is an intracellular bulk degradation process whereby cytoplasmic proteins and organelles are degraded and recycled through lysosomes. In the heart, autophagy plays a homeostatic role at basal levels, and the absence of autophagy causes cardiac dysfunction and the development of cardiomyopathy. Autophagy is induced during myocardial ischemia and further enhanced by reperfusion. Although induction of autophagy during the ischemic phase is protective, further enhancement of autophagy during the reperfusion phase may induce cell death and appears to be detrimental. In this review we discuss the functional significance of autophagy and the underlying signaling mechanism in the heart during ischemia/reperfusion.
BackgroundIt is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations.MethodsThis prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2).ResultsFrom August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age.ConclusionThis was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.