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Jia Yin, Fushin X. Yu; Role of Histone Acetylation in Corneal Epithelial Wound Healing and Diabetic Keratopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5307.
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Patients with diabetes are at an increased risk for developing corneal complications and potential vision loss. Histone modifications are known to regulate gene expression and have been suggested as a target of hyperglycemia and a cause of diabetic complications. Our current objective is to investigate the role of histone acetylation in corneal epithelial wound healing and diabetic keratopathy.
Human corneal epithelial cells (CEC) were cultured in media containing either 5 mM or 25 mM glucose for 10 days. Histone acetylation and expression of histone deacetylases (HDAC) were analyzed by Western blotting. Effects of HDAC inhibitor valproic acid (VPA) on wound healing were determined in porcine corneal organ culture and CEC scratch wound models. AStreptozotocin-induced type I diabetes rat model was also utilized. Eight weeks after diabetes induction, a circular central corneal epithelial abrasion was created and re-epithelialization was monitored. CEC were collected from diabetic and age-matched normal rats for determination of histone acetylation.
Human CEC cultured in high glucose condition demonstrated increased acetylation of histone 3 and unchanged levels of HDAC1-3. CEC isolated from rats with 8 weeks of diabetes also demonstrated higher level of histone 3 acetylation, as compared with the age-matched control rats. HDAC inhibitor VPA significantly down-regulated the expression of HDAC, up-regulated histone 3 acetylation, and accelerated CEC wound closure in vitro. While hyperglycemia retarded wound healing in cultured porcine corneas, VPA rescued the hyperglycemia-impaired wound closure. Epidermal growth factor receptor (EGFR) ligand, heparin-binding EGF-like growth factor (HB-EGF), up-regulated histone 3 acetylation and enhanced scratch wound closure.
Histone acetylation plays a role in corneal epithelial wound healing and is a potential target of hyperglycemia. HDAC inhibitors via modulating histone acetylation may provide therapeutic potentials to ease diabetic keratopathy or delayed diabetic wound healing.
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