title: p66(Shc)-induced redox changes drive endothelial insulin resistance.
abstract: OBJECTIVE
  Obesity-induced insulin resistance (IR) precipitates cardiovascular disease (CVD). Impairment of insulin signalling in the endothelium is emerging as a trigger of IR but the underlying mechanisms remain elusive. The mitochondrial adaptor p66(Shc) drives endothelial dysfunction via reactive oxygen species (ROS) generation. This study investigates p66(Shc) role in obesity-induced impairment of endothelial insulin signalling.
  
  
  METHODS
  All experiments were performed in leptin-deficient (Lep(Ob/Ob)) and wild-type (WT) mice.
  
  
  RESULTS
  Endothelium-dependent relaxations to insulin were blunted in Lep(Ob/Ob) as compared to WT. Interestingly, in vivo gene silencing of p66(Shc) restored insulin response via IRS-1/Akt/eNOS pathway. Furthermore, p66(Shc) knockdown in endothelial cells isolated from Lep(Ob/Ob) mice attenuated ROS production, free fatty acids (FFA) oxidation and prevented dysregulation of redox-sensitive pathways such as nuclear factor-kappa-B (NF-kB), AGE precursor methylglyoxal and PGI2 synthase.
  
  
  CONCLUSIONS
  Targeting endothelial p66(Shc) may represent a promising strategy to prevent IR and CVD in obese individuals.
authors.affiliation: Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden; Cardiology, Department of Clinical and Molecular Medicine, University of Rome "Sapienza", Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Paneni
authors.affiliation: Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Sarah
authors.initials: S
authors.lastname: Costantino
authors.affiliation: Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. Electronic address: francesco.cosentino@ki.se.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cosentino
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D020738:Leptin / Q000172:deficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010656:Phenylephrine / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020738:Leptin; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013481:Superoxides; D010656:Phenylephrine; D011765:Pyruvaldehyde; D003577:Cytochrome P-450 Enzyme System; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase
keywords: Cardiovascular disease; Endothelial insulin resistance; Inflammation; Obesity; Oxidative stress