title: Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress and endothelial dysfunction.
abstract: The 66-kDa Src homology 2 domain-containing protein (p66Shc) is a master regulator of reactive oxygen species (ROS). It is expressed in many tissues where it contributes to organ dysfunction by promoting oxidative stress. In the vasculature, p66Shc-induced ROS engenders endothelial dysfunction. Here we show that p66Shc is a direct target of the Sirtuin1 lysine deacetylase (Sirt1), and Sirt1-regulated acetylation of p66Shc governs its capacity to induce ROS. Using diabetes as an oxidative stimulus, we demonstrate that p66Shc is acetylated under high glucose conditions and is deacetylated by Sirt1 on lysine 81. High glucose-stimulated lysine acetylation of p66Shc facilitates its phosphorylation on serine 36 and translocation to the mitochondria, where it promotes hydrogen peroxide production. Endothelium-specific transgenic and global knockin mice expressing p66Shc that is not acetylatable on lysine 81 are protected from diabetic oxidative stress and vascular endothelial dysfunction. These findings show that p66Shc is a target of Sirt1, uncover a unique Sirt1-regulated lysine acetylation-dependent mechanism that governs the oxidative function of p66Shc, and demonstrate the importance of p66Shc lysine acetylation in vascular oxidative stress and diabetic vascular pathophysiology.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; kaikobad-irani@uiowa.edu santosh-kumar@uiowa.edu.|Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA 52242.
authors.forename: Santosh
authors.identifier: 0000-0003-1418-2020
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242.|Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA 52242.
authors.forename: Young-Rae
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242.|Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA 52242.
authors.forename: Ajit
authors.initials: A
authors.lastname: Vikram
authors.affiliation: Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Asma
authors.initials: A
authors.lastname: Naqvi
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242.|Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA 52242.
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242.|Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA 52242.
authors.forename: Modar
authors.initials: M
authors.lastname: Kassan
authors.affiliation: Vascular Biology Section, Cardiovascular Proteomics Center, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Vikas
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Vascular Biology Section, Cardiovascular Proteomics Center, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Bachschmid
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242.|Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA 52242.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Jacobs
authors.affiliation: Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; kaikobad-irani@uiowa.edu santosh-kumar@uiowa.edu.|Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA 52242.
authors.forename: Kaikobad
authors.initials: K
authors.lastname: Irani
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D005947:Glucose / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D034622:RNA Interference; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D056564:Sirtuin 1; D005947:Glucose; D008239:Lysine
keywords: diabetes; lysine acetylation; oxidative stress; p66Shc; sirt1