p66Shc-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.
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p66Shc activation is involved in adipogenesis, insulin resistance, and cardiovascular complications associated with diabetes mellitus.
“Additional work has revealed that p66Shc activation is involved in adipogenesis, insulin resistance and cardiovascular complications associated with diabetes mellitus187–189.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [189]
Vascular p66Shc levels are increased in animal models of obesity and contribute to endothelial insulin resistance, an effect reversed by silencing p66Shc in vivo.
“Moreover, vascular levels of p66Shc were increased in animal models of obesity and had a role in endothelial insulin resistance189, an effect restored when p66Shc was silenced in vivo189.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [189]
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References 23 · Cited by 38
- Authors
- Paneni, F., Costantino, S., & Cosentino, F.
- Affiliations
- Karolinska University Hospital (SE)
- Corresponding author
- Cosentino, Francesco
- Venue
- Atherosclerosis
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 236
- Issue
- 2
- Pages
- 426-429
- ISSN
- 0021-9150 (ISSN-L)
- OpenAlex
- W2164356881
- Cited by
- 38
- References
- 23
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 6 · 2019: 2 · 2018: 3 · 2017: 7 · 2015: 4 · 2014: 2
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Atherosclerosis (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Karolinska Institutet
- Sapienza Università di Roma
- Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2010–2011)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- p66Shc, endothelial insulin resistance, obesity, reactive oxygen species, endothelial dysfunction, leptin deficiency, free fatty acid oxidation, NF-κB, methylglyoxal, cardiovascular disease, gene silencing
- MeSH terms
- Src Homology 2 Domain-Containing, Transforming Protein 1, Animals, Cytochrome P-450 Enzyme System, Endothelium, Vascular, Fatty Acids, Nonesterified, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Oxidation-Reduction, Phenylephrine, Pyruvaldehyde, Superoxides, Vasodilation, NF-kappa B, Reactive Oxygen Species, Mice, Knockout, Intramolecular Oxidoreductases, Leptin, RNA Interference, RNA, Small Interfering, Mice, Nitric Oxide Synthase Type III, Shc Signaling Adaptor Proteins, Molecular Targeted Therapy
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