title: NAD(+)-dependent SIRT1 deactivation has a key role on ischemia-reperfusion-induced apoptosis.
abstract: Ischemia-reperfusion (IR) leads to severe organ injury and dysfunction. Sirtuins (SIRTs) are a family of histone deacetylases (HDACs) that require nicotinamide adenine dinucleotide (NAD(+)) for the deacetylation reaction. SIRTs play a major role in counteracting cellular stress and apoptosis. This study aimed to investigate the mechanisms of heart protection against apoptosis by SIRTs and the molecular pathways involved in SIRTs regulation and function in a rat model of IR injury. Hearts of male Wistar-Kyoto rats were subjected to 30-min ischemia followed by reperfusion up to 6h. IR increased cardiomyocyte apoptosis; the cleavage of caspase 3, induced a transient upregulation of SIRT1 and downregulation of SIRT6 expression, but decreased SIRT1 activity and reduced NAD(+) content. IR also increased forkhead box protein O1 (FoxO1) expression and FoxO1 binding to SIRT1 promoter region. Resveratrol restored SIRT1 activity and NAD(+) level by an AMPK-dependent mechanism, reduced cardiomyocyte apoptosis, and attenuated caspase 3 cleavage via heat shock factor-1 deacetylation and heat shock protein (HSP) expression upregulation. Our data show new potential molecular mechanisms of up and downstream regulation of SIRT1 in IR. The interplay among FoxO1, SIRT1, NAD(+), AMPK, HSP, and SIRT6 depicts a complex molecular network that protects the heart from apoptosis during IR and may be susceptible to therapeutic interventions.
authors: Department of Medicine-DIMED, University of Padova, Italy.
authors: Arianna
authors: A
authors: Cattelan
authors: Department of Medicine-DIMED, University of Padova, Italy.
authors: Giulio
authors: G
authors: Ceolotto
authors: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Italy.
authors: Sergio
authors: S
authors: Bova
authors: Venetian Institute of Molecular Medicine, Padova, Italy.
authors: Mattia
authors: M
authors: Albiero
authors: Department of Medicine-DIMED, University of Padova, Italy.
authors: Maniselvan
authors: M
authors: Kuppusamy
authors: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Italy.
authors: Sara
authors: S
authors: De Martin
authors: Department of Medicine-DIMED, University of Padova, Italy.
authors: Andrea
authors: A
authors: Semplicini
authors: Department of Medicine-DIMED, University of Padova, Italy; Venetian Institute of Molecular Medicine, Padova, Italy.
authors: Gian Paolo
authors: GP
authors: Fadini
authors: Department of Medicine-DIMED, University of Padova, Italy.
authors: Saula Vigili
authors: SV
authors: de Kreutzenberg
authors: Department of Medicine-DIMED, University of Padova, Italy; Venetian Institute of Molecular Medicine, Padova, Italy. Electronic address: angelo.avogaro@unipd.it.
authors: Angelo
authors: A
authors: Avogaro
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D053148:Caspase 3 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D000076249:Heat Shock Transcription Factors; D000067268:Isolated Heart Preparation; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009243:NAD / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011921:Rats, Inbred WKY; D000077185:Resveratrol; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D000071161:Forkhead Box Protein O1
chemical_list: D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D005947:Glucose; D000076249:Heat Shock Transcription Factors; D009243:NAD; D009419:Nerve Tissue Proteins; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins; D013267:Stilbenes; D014157:Transcription Factors; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C505410:Casp3 protein, rat; C488368:Sirt1 protein, rat; C560607:sirtuin 6, rat
keywords: Apoptosis; Caspase 3; Compound C (PubChem: CID 11524144); FK-866 (PubChem: CID 6914657); NAD(+); Reperfusion injury; Resveratrol (PubChem: CID 445154); SIRTs; Sirtinol (PubChem: CID 5717148); alpha-d-Glucose (PubChem: CID 79025); d-mannitol (PubChem: CID 6251)