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Emilie HECKEL, Sheetal Pundir, jin sung-kim, Jean-Sebastien Joyal; Improving autophagy rescues pathologic angiogenesis and vision in a murine model of AMD. Invest. Ophthalmol. Vis. Sci. 2017;58(8):813.
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© ARVO (1962-2015); The Authors (2016-present)
Drivers of pathological angiogenesis that contribute to vision loss in age related macular degeneration (AMD) are not well understood. Dysregulated glucose and lipid metabolism in photoreceptors create a fuel shortage that attract pathological neovessels in an attempt to reinstate energy homeostasis in AMD. Fuel deficient photoreceptors are capable of autophagy, the mechanism by which cells recycle intracellular nutrients to fuel mitochondria. We hypothesize that deregulated autophagy in a mice model of AMD exacerbates the energy failure of photoreceptors leading to pathological angiogenesis and blindness.
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). Electroretinograms (ERG) were recorded from Vldlr-/- and WT mice, treated or not with various autophagy enhancing drugs (P7 to P30). Scotopic recordings were performed under increasing light intensities. Photopic recordings were performed following 3 min light adaptation intervals.
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-II, p62) and lipid metabolism (PPARα) were suppressed in Vldlr-/- mice compared to 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. Pharmacological agonist that improve autophagy significantly reduced neovascular lesions in Vldlr-/- mice (57%; p<0.05) and improved their vision by ERG (32% higher a-wave and 28% reduction in a-wave latency; p<0.05).
Dysregulated autophagy may therefore contribute to the onset of AMD-like lesions by decreasing fuel supply to mitochondria. Means of regulating autophagy may offer a novel therapeutic strategy to alleviate neovascular AMD and improve vision.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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