title: Exendin-4 induces extracellular-superoxide dismutase through histone H3 acetylation in human retinal endothelial cells.
abstract: Extracellular-superoxide dismutase (genetic nameSOD3) is a secreted anti-oxidative enzyme, and its presence in vascular walls may play an important role in protecting the vascular system against oxidative stress. Oxidative stress has been implicated in the pathogenesis of diabetic retinopathy; therefore, increases in extracellular-superoxide dismutase have been suggested to inhibit the progression of diabetic retinopathy. Incretin-based drugs such as glucagon-like peptide-1 receptor agonists are used in the treatment of type 2 diabetes. Glucagon-like peptide-1 receptor agonists are expected to function as extrapancreatic agents because the glucagon-like peptide-1 receptor is expressed not only in pancreatic tissues, but also in many other tissue types. We herein demonstrated that exendin-4, a glucagon-like peptide-1 receptor agonist, induced the expression of extracellular-superoxide dismutase in human retinal microvascular endothelial cells through epigenetic regulation. The results of the present study demonstrated that exendin-4 induced the expression of extracellular-superoxide dismutase through histone H3 acetylation at theSOD3proximal promoter region. Moreover, plasma extracellular-superoxide dismutase concentrations in diabetic patients were elevated by incretin-based therapies. Therefore, incretin-based therapies may exert direct extrapancreatic effects in order to protect blood vessels by enhancing anti-oxidative activity.
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ohashi
authors.affiliation: Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Nishida
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kamiya
authors.affiliation: Department of Diabetes and Endocrinology, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suwa
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Diabetes and Endocrinology, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Takeda
authors.affiliation: Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Adachi
keywords: diabetic retinopathy; epigenetics; exendin-4; extracellular-superoxide dismutase; incretin-based therapy