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Ye Wang, Xiaowen Zhao, Daling Shi, Peng Chen, Yang Yu, Lingling Yang, Lixin Xie; Overexpression of SIRT1 Promotes High Glucose–Attenuated Corneal Epithelial Wound Healing via p53 Regulation of the IGFBP3/IGF-1R/AKT Pathway. Invest. Ophthalmol. Vis. Sci. 2013;54(5):3806-3814. doi: 10.1167/iovs.13-12091.
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Toinvestigate how Sirtuin (silent mating type information regulation 2 homolog) 1 (SIRT1) promotes high glucose–attenuated corneal epithelial wound healing.
The effects of high glucose on SIRT1 expression were assessed in primary human corneal epithelial cells (CECs) in treatment of 5 mM d-glucose (normal glucose [NG]) and 25 mM d-glucose (high glucose [HG]) and corneas from Ins2Akita/+ mice by Western blotting. The osmotic pressure of the NG medium was adjusted to that of the HG medium by adding 20 mM mannitol. Pifithrin-α (PFT-α) was used to inhibit the expression of p53 and an adenovirus was used for overexpression of SIRT1 in vivo and in vitro. How overexpression of SIRT1 promotes HG-attenuated corneal epithelial wound healing via p53 regulation of the IGFBP3 (insulin-like growth factor binding protein-3)/IGF-1 (insulin-like growth factor-1)/AKT pathway was investigated in CECs and Ins2Akita/+ mice.
HG induced the downregulation of SIRT1 and the upregulation of p53 acetylation in primary human CECs and corneas from Ins2Akita/+ mice. The results of cell migration assay and corneal wound healing from Ins2Akita/+ mice demonstrated that SIRT1 overexpression strongly promoted wound healing in the presence of HG levels via the downregulation of the IGFBP3 protein. The levels of total p53 expression and acetylated p53 decreased dramatically in the presence of PFT-α, whereas the IGF-1R/AKT pathway was activated in CECs. The results of cell migration assay suggested this posttranslational modification of p53 was involved in the response to cell injury under HG conditions in CECs.
The molecular mechanism by which SIRT1 promotes corneal epithelial wound healing was involved in an enhancement of the IGFBP3/IGF-1/AKT pathway through the deacetylation of p53. This study also suggests that SIRT1 has a protective role in the pathogenesis of diabetic keratopathy.
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