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Jean-Sebastien Joyal, Sheetal Pundir, Jin Sung Kim, Emilie HECKEL, Nicholas Kim, Perrine Gaub; Glycolysis promotes retinal revascularization in a mouse model of proliferative retinopathy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2450. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Sirtuin-3 (Sirt3) is a mitochondrial deacetylase that regulates key enzymes of energy metabolism. In mitochondria, Sirt3 favors oxidative phosphorylation at the expense of glycolysis. However, glycolysis may provide a proliferative advantage through the Warburg effect, as seen in tumors. We therefore hypothesize that loss of Sirt3 shifts retinal energy metabolism towards glycolysis and promotes endothelial cell proliferation, enhancing retinal vascular regeneration.
Sirt3-/- and wild-type mice were used in a mouse model of oxygen-induced retinopathy (OIR). Eyes were collected from postnatal day 12 to 17, processed for flat mount, bromo-deoxyuridine labelling and immunostaining, the collection of proteins and RNA. Trace amount of 2-deoxyglucose (2DG) was injected to OIR mice from P11 to P16 to measure glucose uptake in retina. Aortic rings and spheroids were cultured ex-vivo to quantify vascular sprouts.
Vaso-obliteration (VO) at P17 of WT (n=23) and Sirt3-/- (n=26) retinas exposed to OIR showed 53% reduction in VO (P<0.0001), suggesting an increased revascularization rate. In line, pathological neovascularization was decreased by 40% (NV; P<0.0051) in Sirt3-/- retinas. More filopodias were observed per tip cells of Sirt3-/- retinas (P<0.0001; WT: n=23, Sirt3-/-: n=18). Retinal glucose uptake (3H-2DG) was also increased by 50% in Sirt3-/- mice (P=0.0014, n=8) compared to WT following OIR, likely contributing to the Warburg effect. Conversely, glycolysis inhibitor (3PO, 30-40 µM) abrogates vessel sprouting (n=7-12, P<0.001) in aortic ring, highlighting the importance of glycolysis in angiogenesis.
Here we show that loss of Sirt3 improves retinal revascularization by shifting metabolism towards glycolysis. The increase in glycolysis in Sirt3-/- retinas may supply biosynthetic precursors required for prompt retinal revascularization, preventing vision loss.
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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