p66(Shc)-induced redox changes drive endothelial insulin resistance

Atherosclerosis. 2014 Oct;236(2):426-9. doi: 10.1016/j.atherosclerosis.2014.07.027. Epub 2014 Aug 5.

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.

Keywords: Cardiovascular disease; Endothelial insulin resistance; Inflammation; Obesity; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme System / metabolism
  • Endothelium, Vascular / physiopathology*
  • Fatty Acids, Nonesterified / metabolism
  • Insulin / pharmacology
  • Insulin Resistance / physiology*
  • Intramolecular Oxidoreductases / metabolism
  • Leptin / deficiency
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Molecular Targeted Therapy
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Obesity / genetics
  • Obesity / metabolism
  • Oxidation-Reduction
  • Phenylephrine / pharmacology
  • Pyruvaldehyde / metabolism
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Reactive Oxygen Species
  • Shc Signaling Adaptor Proteins / antagonists & inhibitors
  • Shc Signaling Adaptor Proteins / deficiency
  • Shc Signaling Adaptor Proteins / physiology*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Superoxides / metabolism
  • Vasodilation / drug effects

Substances

  • Fatty Acids, Nonesterified
  • Insulin
  • Leptin
  • NF-kappa B
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Superoxides
  • Phenylephrine
  • Pyruvaldehyde
  • Cytochrome P-450 Enzyme System
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Intramolecular Oxidoreductases
  • prostacyclin synthetase