γ-secretase inhibition of murine choroidal neovascularization is associated with reduction of superoxide and proinflammatory cytokines

Xiaoping Qi, Jun Cai, Qing Ruan, Li Liu, Sanford L. Boye, Zhijuan Chen, William W. Hauswirth, Renee C. Ryals, Lynn Shaw, Sergio Caballero, Maria B. Grant, Michael E. Boulton

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Purpose. This study aimed to determine whether upregulation of γ-secretase could inhibit laser-induced choroidal neovascularization (CNV) and if this was associated with a reduction in both oxidative stress and proinflammatory cytokines. Methods. γ-Secretase, or its catalytic subunit presenilin 1 (PS1), were upregulated by exposure to either pigment epithelial derived factor (PEDF) or an AAV2 vector containing a PS1 gene driven by a vascular endothelial-cadherin promoter. Retinal endothelial cells were infected with AAV2 or exposed to PEDF in the presence or absence of VEGF and in vitro angio-genesis determined. Mouse eyes either received intravitreal injection of PEDF, DAPT (a γ-secretase inhibitor) or PEDF + DAPT at the time of laser injury, or AAV2 infection 3 weeks before receiving laser burns. Lesion volume was determined 14 days post laser injury. Superoxide generation, antioxidant activity and the production of proinflammatory mediators were assessed. Knockdown of γ-secretase was achieved using siRNA. Results. γ-Secretase upregulation and PS1 overexpression suppressed VEGF-induced in vitro angiogenesis and in vivo laser-induced CNV. This was associated with a reduction in the expression of VEGF and angiogenin 1 together with reduced superoxide anion generation and an increase in MnSOD compared with untreated CNV eyes. PS1 overexpression reduced proinflammatory factors and microglial activation in eyes with CNV compared with control. siRNA inhibition of γ-secretase resulted in increased angiogenesis. Conclusions. γ-Secretase, and in particular PS1 alone, are potent regulators of angiogenesis and this is due in part to stabilizing endogenous superoxide generation and reducing proinflammatory cytokine expression uring CNV.

Original languageEnglish (US)
Pages (from-to)574-585
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume53
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

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Choroidal Neovascularization
Amyloid Precursor Protein Secretases
Presenilin-1
Superoxides
Cytokines
Lasers
Vascular Endothelial Growth Factor A
Small Interfering RNA
Up-Regulation
Intravitreal Injections
Wounds and Injuries
Burns
Catalytic Domain
Oxidative Stress
Endothelial Cells
Antioxidants
Infection
Genes

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

γ-secretase inhibition of murine choroidal neovascularization is associated with reduction of superoxide and proinflammatory cytokines. / Qi, Xiaoping; Cai, Jun; Ruan, Qing; Liu, Li; Boye, Sanford L.; Chen, Zhijuan; Hauswirth, William W.; Ryals, Renee C.; Shaw, Lynn; Caballero, Sergio; Grant, Maria B.; Boulton, Michael E.

In: Investigative Ophthalmology and Visual Science, Vol. 53, No. 2, 02.2012, p. 574-585.

Research output: Contribution to journalArticle

Qi, X, Cai, J, Ruan, Q, Liu, L, Boye, SL, Chen, Z, Hauswirth, WW, Ryals, RC, Shaw, L, Caballero, S, Grant, MB & Boulton, ME 2012, 'γ-secretase inhibition of murine choroidal neovascularization is associated with reduction of superoxide and proinflammatory cytokines', Investigative Ophthalmology and Visual Science, vol. 53, no. 2, pp. 574-585. https://doi.org/10.1167/iovs.11-8728
Qi, Xiaoping ; Cai, Jun ; Ruan, Qing ; Liu, Li ; Boye, Sanford L. ; Chen, Zhijuan ; Hauswirth, William W. ; Ryals, Renee C. ; Shaw, Lynn ; Caballero, Sergio ; Grant, Maria B. ; Boulton, Michael E. / γ-secretase inhibition of murine choroidal neovascularization is associated with reduction of superoxide and proinflammatory cytokines. In: Investigative Ophthalmology and Visual Science. 2012 ; Vol. 53, No. 2. pp. 574-585.
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abstract = "Purpose. This study aimed to determine whether upregulation of γ-secretase could inhibit laser-induced choroidal neovascularization (CNV) and if this was associated with a reduction in both oxidative stress and proinflammatory cytokines. Methods. γ-Secretase, or its catalytic subunit presenilin 1 (PS1), were upregulated by exposure to either pigment epithelial derived factor (PEDF) or an AAV2 vector containing a PS1 gene driven by a vascular endothelial-cadherin promoter. Retinal endothelial cells were infected with AAV2 or exposed to PEDF in the presence or absence of VEGF and in vitro angio-genesis determined. Mouse eyes either received intravitreal injection of PEDF, DAPT (a γ-secretase inhibitor) or PEDF + DAPT at the time of laser injury, or AAV2 infection 3 weeks before receiving laser burns. Lesion volume was determined 14 days post laser injury. Superoxide generation, antioxidant activity and the production of proinflammatory mediators were assessed. Knockdown of γ-secretase was achieved using siRNA. Results. γ-Secretase upregulation and PS1 overexpression suppressed VEGF-induced in vitro angiogenesis and in vivo laser-induced CNV. This was associated with a reduction in the expression of VEGF and angiogenin 1 together with reduced superoxide anion generation and an increase in MnSOD compared with untreated CNV eyes. PS1 overexpression reduced proinflammatory factors and microglial activation in eyes with CNV compared with control. siRNA inhibition of γ-secretase resulted in increased angiogenesis. Conclusions. γ-Secretase, and in particular PS1 alone, are potent regulators of angiogenesis and this is due in part to stabilizing endogenous superoxide generation and reducing proinflammatory cytokine expression uring CNV.",
author = "Xiaoping Qi and Jun Cai and Qing Ruan and Li Liu and Boye, {Sanford L.} and Zhijuan Chen and Hauswirth, {William W.} and Ryals, {Renee C.} and Lynn Shaw and Sergio Caballero and Grant, {Maria B.} and Boulton, {Michael E.}",
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T1 - γ-secretase inhibition of murine choroidal neovascularization is associated with reduction of superoxide and proinflammatory cytokines

AU - Qi, Xiaoping

AU - Cai, Jun

AU - Ruan, Qing

AU - Liu, Li

AU - Boye, Sanford L.

AU - Chen, Zhijuan

AU - Hauswirth, William W.

AU - Ryals, Renee C.

AU - Shaw, Lynn

AU - Caballero, Sergio

AU - Grant, Maria B.

AU - Boulton, Michael E.

PY - 2012/2

Y1 - 2012/2

N2 - Purpose. This study aimed to determine whether upregulation of γ-secretase could inhibit laser-induced choroidal neovascularization (CNV) and if this was associated with a reduction in both oxidative stress and proinflammatory cytokines. Methods. γ-Secretase, or its catalytic subunit presenilin 1 (PS1), were upregulated by exposure to either pigment epithelial derived factor (PEDF) or an AAV2 vector containing a PS1 gene driven by a vascular endothelial-cadherin promoter. Retinal endothelial cells were infected with AAV2 or exposed to PEDF in the presence or absence of VEGF and in vitro angio-genesis determined. Mouse eyes either received intravitreal injection of PEDF, DAPT (a γ-secretase inhibitor) or PEDF + DAPT at the time of laser injury, or AAV2 infection 3 weeks before receiving laser burns. Lesion volume was determined 14 days post laser injury. Superoxide generation, antioxidant activity and the production of proinflammatory mediators were assessed. Knockdown of γ-secretase was achieved using siRNA. Results. γ-Secretase upregulation and PS1 overexpression suppressed VEGF-induced in vitro angiogenesis and in vivo laser-induced CNV. This was associated with a reduction in the expression of VEGF and angiogenin 1 together with reduced superoxide anion generation and an increase in MnSOD compared with untreated CNV eyes. PS1 overexpression reduced proinflammatory factors and microglial activation in eyes with CNV compared with control. siRNA inhibition of γ-secretase resulted in increased angiogenesis. Conclusions. γ-Secretase, and in particular PS1 alone, are potent regulators of angiogenesis and this is due in part to stabilizing endogenous superoxide generation and reducing proinflammatory cytokine expression uring CNV.

AB - Purpose. This study aimed to determine whether upregulation of γ-secretase could inhibit laser-induced choroidal neovascularization (CNV) and if this was associated with a reduction in both oxidative stress and proinflammatory cytokines. Methods. γ-Secretase, or its catalytic subunit presenilin 1 (PS1), were upregulated by exposure to either pigment epithelial derived factor (PEDF) or an AAV2 vector containing a PS1 gene driven by a vascular endothelial-cadherin promoter. Retinal endothelial cells were infected with AAV2 or exposed to PEDF in the presence or absence of VEGF and in vitro angio-genesis determined. Mouse eyes either received intravitreal injection of PEDF, DAPT (a γ-secretase inhibitor) or PEDF + DAPT at the time of laser injury, or AAV2 infection 3 weeks before receiving laser burns. Lesion volume was determined 14 days post laser injury. Superoxide generation, antioxidant activity and the production of proinflammatory mediators were assessed. Knockdown of γ-secretase was achieved using siRNA. Results. γ-Secretase upregulation and PS1 overexpression suppressed VEGF-induced in vitro angiogenesis and in vivo laser-induced CNV. This was associated with a reduction in the expression of VEGF and angiogenin 1 together with reduced superoxide anion generation and an increase in MnSOD compared with untreated CNV eyes. PS1 overexpression reduced proinflammatory factors and microglial activation in eyes with CNV compared with control. siRNA inhibition of γ-secretase resulted in increased angiogenesis. Conclusions. γ-Secretase, and in particular PS1 alone, are potent regulators of angiogenesis and this is due in part to stabilizing endogenous superoxide generation and reducing proinflammatory cytokine expression uring CNV.

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