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Nobuyoshi Kitaichi, Anton Lennikov, Satoru Kase, Kousuke Noda, Yukihiro Horie, Shigeaki Ohno, Susumu Ishida; Induction of heat shock protein 70 ameliorates ultraviolet-induced photokeratitis in mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3905. doi: https://doi.org/.
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Background and Puropose: Acute ultraviolet (UV) B exposure causes photokeratitis and induces apoptosis in corneal cells. Geranylgeranylacetone (GGA) is an acyclic polyisoprenoid that induces the expression of heat shock protein (HSP) 70, a soluble intracellular protein expressed in various tissues, including the eyes. HSPs function as intracellular chaperones, protecting cells against various stress conditions. Though the right part of the GGA molecular structure is similar to that of vitamin K, this cannot fully explain the effects of GGA on various tissues. Also, the relationship between HSP70 expression and corneal damage is not known. In the present study, we examined whether the induction of HSP70 has therapeutic effects on UV-photokeratitis in mice.
Methods: C57BL/6 mice were divided into four groups, GGA-treated (500 mg/kg/mouse) and UVB-exposed (400mJ/cm2), GGA-untreated and UVB-exposed, GGA-treated but not UVB-exposed, and naïve. Eyeballs were collected 24 hours after irradiation, and corneas were stained with hematoxylin-eosin (H&E), TUNEL, anti-HSP70, and phospho-(serine/threonine) Akt substrate antibody.
Results: The irradiated corneal epithelium was significantly thicker in the eyes of mice treated with GGA as compared with those given vehicle alone (P<0.01). Significantly fewer TUNEL-positive cells were observed in the eyes of GGA-treated mice than in controls after irradiation (P<0.01). Corneal HSP70 levels were elevated by UV exposure alone. HSP70 expression further increased in irradiated mice when treated with GGA (P<0.05). Phospho-(Ser/Ther) Akt substrate expression was increased in corneas after irradiation when they were treated with GGA.
Conclusion: It was shown that GGA administration induced HSP70 in the eye, and HSP70 was induced more obviously under UVB stress condition. HSP70 activates Akt phosphorylation, and inhibiting Akt dephosphorylation as well as the further activation of cell death pathways. It was indicated that HSP70 induced by GGA administration suppresses cell death signals by activating Akt phosphorylation and inhibiting its dephosphorylation in corneas on UV exposure.
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