September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Dysregulated autophagy contributes to pathological angiogenesis in a mice model of retinal angiomatous proliferation.
Heckel E, Pundir S, Patel G, Kim JS, Lacombe MJ, Saba N, Fredrick T, Sun Y, Smith LEH, Joyal JS
Author Affiliations & Notes
  • Emilie HECKEL
    Pharmacology, CHU Sainte-Justine, MONTREAL, Quebec, Canada
  • Sheetal Pundir
    Pharmacology, CHU Sainte-Justine, MONTREAL, Quebec, Canada
  • Gauri Patel
    Pharmacology, CHU Sainte-Justine, MONTREAL, Quebec, Canada
  • Jin Kim Suang
    Pharmacology, CHU Sainte-Justine, MONTREAL, Quebec, Canada
  • Lacombe Marie Josee
    Pharmacology, CHU Sainte-Justine, MONTREAL, Quebec, Canada
  • Nicholas Saba
    childrens.harvard, Boston, Massachusetts, United States
  • Thomas Fredrick
    childrens.harvard, Boston, Massachusetts, United States
  • Lois E H Smith
    childrens.harvard, Boston, Massachusetts, United States
  • Jean-Sebastien Joyal
    Pharmacology, CHU Sainte-Justine, MONTREAL, Quebec, Canada
  • Footnotes
    Commercial Relationships   Emilie HECKEL, None; Sheetal Pundir, None; Gauri Patel, None; Jin Kim Suang, None; Lacombe Marie Josee, None; Nicholas Saba, None; Thomas Fredrick, None; Lois Smith, None; Jean-Sebastien Joyal, None
  • Footnotes
    Support  NIH EY024868, EY017017, EY022275, P01 HD18655, Lowy Medical Research Institute, European Commission FP7 project 305485 PREVENT-ROP (LEHS); Burroughs Wellcome Fund Career Award for Medical Scientists, Fondation Fighting Blindness, CIHR (143077), Fonds de Recherche du Québec – Santé (FRQS), Canadian Child Health Clinician Scientist Program, and CIHR New Investigator Award (JSJ)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3640. doi:
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    • Get Citation

      Emilie HECKEL, Sheetal Pundir, Gauri Patel, Jin Kim Suang, Lacombe Marie Josee, Nicholas Saba, Thomas Fredrick, Lois E H Smith, Jean-Sebastien Joyal; Dysregulated autophagy contributes to pathological angiogenesis in a mice model of retinal angiomatous proliferation.
      Heckel E, Pundir S, Patel G, Kim JS, Lacombe MJ, Saba N, Fredrick T, Sun Y, Smith LEH, Joyal JS
      . Invest. Ophthalmol. Vis. Sci. 2016;57(12):3640.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Dysregulated autophagy has been associated with lipofucin accumulation, mitochondrial damage and susceptibility to oxidative stress, which in turn contribute to age-related macular degeneration (AMD). Moreover, degradation of lipids by autophagy may help fuel mitochondrial β-oxidation to produce energy. Yet, whether dysregulated autophagy is a cause or a consequence of AMD remains unknown. Here we investigate the role of autophagy in a mice model of retinal angiomatous proliferation (RAP), a subtype of AMD.

Methods : Subretinal vascular lesions of Vldlr-/- mice were characterized by confocal imaging of lectin-stained retinal flat mounts. Markers of autophagy and energy metabolism were assessed by qRT-PCR, Western blot and immunofluorescence. Retinal metabolite profiling was quantified by liquid chromatography and tandem mass spectrometry (LC/MS/MS).

Results : Very low-density lipoprotein receptor (VLDLR) is expressed in photoreceptors and facilitates the uptake of triglyceride-derived fatty acids. Vldlr-/- mice therefore present a relative fuel shortage in lipid. Paradoxically, markers of autophagy (Atg5, LC3, Vsp11) and lipid metabolism (PPARα) were suppressed in Vldlr-/- mice compared to wild-type control (P<0.0006, n=7-12). Moreover, key Krebs cycle metabolite α-ketoglutarate (KG) was suppressed (P<0.007, n=11-15). We confirmed previous findings that low α-KG levels promote hypoxia-induced factor-1α (Hif1α) stabilization and vascular endothelial growth factor (Vegfa) secretion by starved Vldlr-/- photoreceptors, attracting neovessels to reinstate energy homeostasis.

Conclusions : Dysregulated autophagy may therefore contribute to the onset of RAP-like lesions by decreasing fuel supply to mitochondria. Means of regulating autophagy may offer a novel therapeutic strategy to alleviate neovascular AMD.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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