title: SIRT1-mediated acute cardioprotection.
abstract: Overexpression studies have revealed a role for silent information regulator of transcription 1 (SIRT1) lysine deacetylase in cardioprotection against ischemia-reperfusion injury via long-term transcriptional effects. However, short-term SIRT1-mediated lysine deacetylation, within the context of acute cardioprotection, is poorly understood. In this study, the role of SIRT1 in the acute cardioprotective paradigm of first window ischemic preconditioning (IPC) was studied using SIRT1-deficient (SIRT1(+/-)) and SIRT1-overexpressing (SIRT1(+++)) mice. In wild-type hearts, cytosolic lysine deacetylation was observed during IPC, and overacetylation was observed upon pharmacological SIRT1 inhibition. Consistent with a role for SIRT1 in IPC, SIRT1(+/-) hearts could not be preconditioned and exhibited increased cytosolic lysine acetylation. Furthermore, SIRT1(+++) hearts were endogenously protected against ischemia-reperfusion injury and exhibited decreased cytosolic acetylation. Both of these effects in SIRT1(+++) mice were reversed by pharmacological SIRT1 inhibition on an acute timescale. Several downstream targets of SIRT1 were examined, with data suggesting possible roles for endothelial nitric oxide synthase phosphorylation, NF-κB, and stimulation of autophagy. In conclusion, these data suggest that SIRT1, acting on nontranscriptional targets, is required for cardioprotection by acute IPC and that SIRT1-dependent lysine deacetylation occurs during IPC and may play a role in cardioprotective signaling.
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
mesh_terms: D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D003600:Cytosol / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control; D009243:NAD / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009243:NAD; D013482:Superoxide Dismutase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D008239:Lysine