ArticleProceedings of the National Academy of Sciences of the United States of America2017
Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress and endothelial dysfunction.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.
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Who cites it
67 citing papers in PubMed, 1 synthesis or guideline pooled it, 113 citations in OpenAlex.
- Targeting epigenetics and non-coding RNAs in atherosclerosis: from mechanisms to therapeutics.Pharmacology & therapeutics · 2019Pooled it
- Mitochondrial-Endothelial Crosstalk in Cardiometabolic Disease: Mechanisms and Translational Opportunities in the Multi-omics Era.Reviews in cardiovascular medicine · 2026Review
- Engineered miR-122 inhibitors preserve endothelial mitochondrial function and prevent vascular dysfunction in obesity-associated prediabetes.Molecular therapy. Nucleic acids · 2026Article
- Epigenetic and O-glycosylation regulation of p66Shc mitigates mitochondrial oxidative stress in aortic dissection.Theranostics · 2026Article
- Beyond Protein Building Blocks: A Review of Biological Roles and Therapeutic Potential of Free Amino Acids.International journal of molecular sciences · 2025Review
- The Role of the PI3K/Akt/mTOR Pathway in Atherosclerosis: Mechanisms, Therapeutic Potential, and Emerging Targeted Treatments.Current atherosclerosis reports · 2025Review
- Non-Ser36 phosphorylated p66Shc inhibits TRPC-dependent and TRPC-independent calcium influx in vascular smooth muscle cells.Biochemical and biophysical research communications · 2025Article
- SIRT1 Prevents Lens Epithelial Cell Senescence During Age-Related Cataract via Regulating p66Shc.Aging cell · 2025Article
- HDACs and Their Inhibitors on Post-Translational Modifications: The Regulation of Cardiovascular Disease.Cells · 2025Review
- The Role of p66Shc in Cancer: Molecular Mechanisms and Therapeutic Implications.Journal of cellular and molecular medicine · 2025Review
- The advances in acetylation modification in senescence and aging-related diseases.Frontiers in physiology · 2025Review
- Exploring the Gut-Mitochondrial Axis: p66Shc Adapter Protein and Its Implications for Metabolic Disorders.International journal of molecular sciences · 2024Review
- Mitochondrial Dysfunction in Endothelial Progenitor Cells: Unraveling Insights from Vascular Endothelial Cells.Biology · 2024Review
- Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications.Frontiers in endocrinology · 2024Review
- In diabetic male Wistar rats, quercetin-conjugated superparamagnetic iron oxide nanoparticles have an effect on the SIRT1/p66Shc-mediated pathway related to cognitive impairment.BMC pharmacology & toxicology · 2023Article
- Mitochondria in endothelial cells angiogenesis and function: current understanding and future perspectives.Journal of translational medicine · 2023Review
- Review
- NADOncogene · 2023Article
- The interplay of inflammation, exosomes and CaCardiovascular diabetology · 2023Review
- Diabetes and Its Cardiovascular Complications: Potential Role of the Acetyltransferase p300.Cells · 2023Review
7 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
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