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P66Shc-SIRT1 Regulation of Oxidative Stress Protects Against Cardio-cerebral Vascular Disease

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Abstract

Growing evidence shows that acute and chronic overproduction of reactive oxygen species (ROS) and increased oxidants under pathophysiologic circumstances are of vital importance in the development of cardio-cerebral vascular diseases (CCVDs). It has been revealed that the impact of ROS can be suppressed by sirtuin 1 (SIRT1), a member of the highly conserved nicotinamide adenine dinucleotide-dependent class III histone deacetylases through protecting endothelial cells from oxidative injury. Plenty of evidences indicate that p66Shc stimulates mitochondrial ROS generation through its oxidoreductase activity and plays a vital role in the pathophysiology of CCVDs. The link between SIRT and p66Shc, though not very clear yet, may be generally illustrated like this: SIRT1 negatively regulates the expression of p66Shc in transcriptional level. In this review, the authors aimed to discuss the link between the pathogenesis of CCVDs, the regulation of ROS, the interrelation between SIRT1 and p66Shc, and the protective effect of the proper regulation of p66Shc/SIRT1 on CCVDs. The imbalance between the elimination and production of ROS can lead to oxidative stress (OS). More and more evidence suggest that ROS pathological overproduction is closely connected to the genesis and growth of CCVDs. P66shc is a gene that controls ROS level, apoptosis induction, and lifespan. Lots of evidence also indicate a role for SIRT1 mediating OS responses through several ways including directly deacetylating some transcription factors that control anti-OS genes. SIRT1 downregulation can lead to a decreased deacetylation of p66shc gene promoter and can then result in p66shc transcription. SIRT1 binds to the promoter of p66Shc where it can deacetylate histone H3, which weakens the transcription and translation of p66shc.

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Acknowledgments

We would like to thank our colleagues at the Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.

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Authors and Affiliations

  1. Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of China

    Xiangyi Kong, Jian Guan, Junji Wei & Renzhi Wang

  2. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Harvard University, 55 Fruit Street, Boston, MA, 02114-3117, USA

    Xiangyi Kong

  3. Department of Neurosurgery, Tangshan Gongren Hospital, Hebei Medical University, 27 Wenhua Road, Tangshan, 063000, People’s Republic of China

    Jun Li

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript, including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Funding Statement

This study was supported by Peking Union Medical College Youth Research Funds (2016) (Project No. 3332016010; grant recipient—Xiangyi Kong) and Peking Union Medical College Graduate Student Innovation Fund (2015, grant recipient—Xiangyi Kong). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Article highlights

• Oxidative stress (OS) is characterized by ROS overproduction and plays a key role in the development of cardio-cerebral vascular diseases (CCVDs).

• SIRT1 negatively regulates OS in vascular endothelial cells by targeting p53, FOXO3, and eNOS for deacetylation.

• P66Shc is one of the three ShcA isoforms with a unique collagen-homology domain (CH2).

• P66Shc protein promotes mitochondrial ROS generation through an oxidoreductase electron transfer reaction with cytochrome c, leading to OS.

• OS-mediated endothelial dysfunction is a critical factor in CCVD development.

• SIRT1 represses P66Shc transcription at the chromatin level by deacetylating histone H3 in the P66Shc promoter region.

• Regulating P66Shc/SIRT1 could plausibly improve endothelial function and inhibit endothelial senescence, and thus offers a possible strategy to prevent or treat CCVD.

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Kong, X., Guan, J., Li, J. et al. P66Shc-SIRT1 Regulation of Oxidative Stress Protects Against Cardio-cerebral Vascular Disease. Mol Neurobiol 54, 5277–5285 (2017). https://doi.org/10.1007/s12035-016-0073-2

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