RGD Reference Report - Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. - Rat Genome Database

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Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure.

Authors: Tanno, M  Kuno, A  Yano, T  Miura, T  Hisahara, S  Ishikawa, S  Shimamoto, K  Horio, Y 
Citation: Tanno M, etal., J Biol Chem. 2010 Jan 20.
RGD ID: 2316169
Pubmed: PMID:20089851   (View Abstract at PubMed)
PMCID: PMC2832987   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M109.090266   (Journal Full-text)

Oxidative stress plays a pivotal role in chronic heart failure. SIRT1, an NAD(+)-dependent histone/protein deacetylase, promotes cell survival under oxidative stress when it is expressed in the nucleus. However, adult cardiomyocytes predominantly express SIRT1 in the cytoplasm, and its function has not been elucidated. The purpose of this study was to investigate the functional role of SIRT1 in the heart and SIRT1's potential use in therapy for heart failure. We investigated the subcellular localization of SIRT1 in cardiomyocytes and its impact on cell survival. SIRT1 accumulated in the nucleus of cardiomyocytes in the failing hearts of TO-2 hamsters, post-myocardial infarction rats, and a dilated cardiomyopathy patient, but not in control healthy hearts. Nuclear but not cytoplasmic SIRT1 induced manganese superoxide dismutase (Mn-SOD), which was further enhanced by resveratrol, and increased the resistance of C2C12 myoblasts to oxidative stress. Resveratrol's enhancement of Mn-SOD levels depended on the level of nuclear SIRT1, and it suppressed the cell death induced by antimycin A or angiotensin II. The cell-protective effects of nuclear SIRT1 or resveratrol were canceled by the Mn-SOD-siRNA or SIRT1-siRNA. The oral administration of resveratrol to TO-2 hamsters increased the Mn-SOD levels in cardiomyocytes, suppressed fibrosis, preserved cardiac function, and significantly improved survival. Thus, the Mn-SOD induced by resveratrol via nuclear SIRT1 reduced oxidative stress and participated in cardiomyocyte protection. SIRT1 activators such as resveratrol could be novel therapeutic tools for the treatment of chronic heart failure.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
myocardial infarction  ISOSirt1 (Rattus norvegicus)2316169; 2316169protein:altered localization:nucleusRGD 
myocardial infarction  IEP 2316169protein:altered localization:nucleusRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to resveratrol  IMP 2316169 RGD 
negative regulation of cardiac muscle cell apoptotic process  IMP 2316169 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
nucleus  IDA 2316169 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Sirt1  (sirtuin 1)

Genes (Mus musculus)
Sirt1  (sirtuin 1)

Genes (Homo sapiens)
SIRT1  (sirtuin 1)


Additional Information