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Ian F. Pitha, Michael B. Sporn, Rajendra S. Apte; Nrf2 Signaling Inhibits Pathologic Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4160.
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© ARVO (1962-2015); The Authors (2016-present)
To test the hypotheses that (1) signaling of the transcription factor Nrf2 suppresses choroidal neovascularization (CNV) and that (2) pharmacologic activation of Nrf2 inhibits CNV formation.
CNV was induced in 6 week-old wild-type (wt) and nrf2 knockout (nrf2-/-) C57Bl/6J mice by rupture of Bruchs membrane using a krypton redcoherent laser. On day 7 after treatment, CNV was visualized using fluorescein angiography and CNV area was quantified using digital imaging software. Choroidal endothelial cell growth from wt and nrf2-/- mice was quantified using a novel, in vitro choroidal explant assay developed in our laboratory. The ability of wt and nrf2-/- macrophages to regulate microvascular endothelial cell growth was assessed by an in vitro coculture assay. To determine whether pharmacologic Nrf2 activation inhibits CNV formation, wt and nrf2-/- mice were treated with vehicle control or the potent Nrf2 activating agent CDDO-Im after rupture of Bruchs membrane.
CNV area was significantly larger in nrf2-/- compared to wt control mice. Choroidal endothelial cell proliferation was not increased in nrf2-/- mice, however, macrophages isolated from nrf2-/- mice exhibited significantly reduced ability to inhibit endothelial cell growth compared to macrophages isolated from wt mice. The Nrf2 activating agent CDDO-Im inhibited CNV formation in a dosage dependent manner. Mice treated with 3 micromole/kg mouse weight CDDO-Im by had significantly reduced CNV area while mice treated with 0.3 micromole/kg did not display significant reduction in CNV. Nrf2-/- mice were resistant to CDDO-Im-mediated inhibition of CNV formation.
Nrf2 signaling suppresses pathologic CNV and is necessary for macrophage-induced inhibition of endothelial cell growth. Pharmacologic induction of Nrf2 signaling inhibits CNV formation in an Nrf2-dependent manner. Taken together these data suggest that activation of Nrf2 signaling has potential to inhibit CNV in diseases such as exudative age-related macular degeneration.
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