title: Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases.
abstract: Previous studies have shown that vitreous stimulates degradation of the tumor suppressor protein p53 and that knockdown of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Kα and -β) abrogates proliferation of p53-deficient cells. The purpose of this study was to determine whether vitreous stimulated expression of PI5P4Kα and -β and whether suppression of PI5P4Kα and -β would inhibit vitreous-induced cellular responses and experimental proliferative vitreoretinopathy (PVR).
  
  
  
  PI5P4Kα and -β encoded by PIP4K2A and 2B, respectively, in human ARPE-19 cells were knocked down by stably expressing short hairpin (sh)RNA directed at human PIP4K2A and -2B. In addition, we rescued expression of PI5P4Kα and -β by re-expressing mouse PIP4K2A and -2B in the PI5P4Kα and -β knocked-down ARPE-19 cells. Expression of PI5P4Kα and -β was determined by Western blot and immunofluorescence. The following cellular responses were monitored: cell proliferation, survival, migration, and contraction. Moreover, the cell potential of inducing PVR was examined in a rabbit model of PVR effected by intravitreal cell injection.
  
  
  
  We found that vitreous enhanced expression of PI5P4Kα and -β in RPE cells and that knocking down PI5P4Kα and -β abrogated vitreous-stimulated cell proliferation, survival, migration, and contraction. Re-expression of mouse PIP4Kα and -β in the human PI5P4Kα and -β knocked-down cells recovered the loss of vitreous-induced cell contraction. Importantly, suppression of PI5P4Kα and -β abrogated the pathogenesis of PVR induced by intravitreal cell injection in rabbits. Moreover, we revealed that expression of PI5P4Kα and -β was abundant in epiretinal membranes from PVR grade C patients.
  
  
  
  The findings from this study indicate that PI5P4Kα and -β could be novel therapeutic targets for the treatment of PVR.
authors.affiliation: Schepens Eye Research Institute, Boston, Massachusetts, United States 2Massachusetts Eye and Ear, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States 4Aier School of Ophthalmology.
authors.forename: Gaoen
authors.initials: G
authors.lastname: Ma
authors.affiliation: Schepens Eye Research Institute, Boston, Massachusetts, United States 2Massachusetts Eye and Ear, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Yajian
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Schepens Eye Research Institute, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Xionggao
authors.initials: X
authors.lastname: Huang
authors.affiliation: Massachusetts Eye and Ear, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Qian
authors.affiliation: Massachusetts Eye and Ear, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Yewlin
authors.initials: Y
authors.lastname: Chee
authors.affiliation: Massachusetts Eye and Ear, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Mukai
authors.affiliation: The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.affiliation: Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Arif
authors.initials: A
authors.lastname: Samad
authors.affiliation: The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Joanne Aiko
authors.initials: JA
authors.lastname: Matsubara
authors.affiliation: Schepens Eye Research Institute, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Andrius
authors.initials: A
authors.lastname: Kazlauskas
authors.affiliation: Schepens Eye Research Institute, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: D'Amore
authors.affiliation: Aier School of Ophthalmology, Central South University, Changsha, Changsha Province, China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Gu
authors.affiliation: Schepens Eye Research Institute, Boston, Massachusetts, United States 3Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Hetian
authors.initials: H
authors.lastname: Lei
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D011817:Rabbits; D012163:Retinal Detachment / Q000517:prevention & control; D018630:Vitreoretinopathy, Proliferative / Q000209:etiology / Q000517:prevention & control*; D014822:Vitreous Body / Q000378:metabolism
chemical_list: C000608224:PI5P4Kbeta protein, mouse; C514871:PIP4K2A protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor)