title: Sirtuin1 over-expression does not impact retinal vascular and neuronal degeneration in a mouse model of oxygen-induced retinopathy.
abstract: Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy.
authors.affiliation: Instituto Nacional de Geriatría, Institutos Nacionales de Salud, México.
authors.forename: Shaday
authors.initials: S
authors.lastname: Michan
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Juan
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hurst
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lucy P
authors.initials: LP
authors.lastname: Evans
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Colman J
authors.initials: CJ
authors.lastname: Hatton
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Dorothy T
authors.initials: DT
authors.lastname: Pei
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Meihua
authors.initials: M
authors.lastname: Ju
authors.affiliation: Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America ; Department of Pharmacology, The University of New South Wales, Kensington, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000009:adverse effects; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012162:Retinal Degeneration / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; C577485:Nes protein, mouse; D064231:Nestin; C525422:SRT1720; D013267:Stilbenes; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C045073:Cre recombinase; D019426:Integrases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol; D010100:Oxygen