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

Francesco Paneni; Sarah Costantino; Francesco Cosentino

doi:10.1016/j.atherosclerosis.2014.07.027

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.

Authors

Francesco Paneni¹, Sarah Costantino², Francesco Cosentino³

Affiliations

¹ Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden; Cardiology, Department of Clinical and Molecular Medicine, University of Rome "Sapienza", Italy.
² Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
³ Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. Electronic address: [email protected].

PMID: 25150941
DOI: 10.1016/j.atherosclerosis.2014.07.027

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