September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Sirt3-deficient retina revascularizes faster by shifting cellular metabolism towards glycolysis in a mouse model of proliferative retinopathy
Author Affiliations & Notes
  • Sheetal Pundir
    Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada
    Research, CHU-St. Justine Hospital, Montreal, Quebec, Canada
  • Emilie Heckel
    Pharmacology, University of Montreal, Montreal, Quebec, Canada
    Research, CHU-St. Justine Hospital, Montreal, Quebec, Canada
  • Jin Kim Suang
    Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada
    Research, CHU-St. Justine Hospital, Montreal, Quebec, Canada
  • Gauri Patel
    Pharmacology, University of Montreal, Montreal, Quebec, Canada
    Research, CHU-St. Justine Hospital, Montreal, Quebec, Canada
  • Lacombe Marie Josee
    Research, CHU-St. Justine Hospital, Montreal, Quebec, Canada
  • Daniel Toledano
    Research, CHU-St. Justine Hospital, Montreal, Quebec, Canada
  • Jean-Sebastien Joyal
    Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada
    Research, CHU-St. Justine Hospital, Montreal, Quebec, Canada
  • Footnotes
    Commercial Relationships   Sheetal Pundir, None; Emilie Heckel, None; Jin Kim Suang, None; Gauri Patel, None; Lacombe Marie Josee, None; Daniel Toledano, None; Jean-Sebastien Joyal, None
  • Footnotes
    Support  CIHR (Canadian Institute of Health Research)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3634. doi:
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      Sheetal Pundir, Emilie Heckel, Jin Kim Suang, Gauri Patel, Lacombe Marie Josee, Daniel Toledano, Jean-Sebastien Joyal; Sirt3-deficient retina revascularizes faster by shifting cellular metabolism towards glycolysis in a mouse model of proliferative retinopathy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3634.

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

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Abstract

Purpose : 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 and promotes endothelial cell proliferation, enhancing retinal vascular regeneration.

Methods : 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 the collection of proteins, RNA, flat mount, bromo-deoxyuridine labelling and immunostaining. Aortic rings were ex-vivo cultured to quantify vascular sprouts. Trace amount of 2-deoxyglucose (2DG) was injected to OIR mice from P11 to P16 to measure glucose uptake in retina.

Results : 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 Sirt3-/- . 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. Tip cells of Sirt3-/- retinas showed 11.75±1.008 filopodias (average±SEM) while the tip cells of WT showed 7.22±0.418 filopodias (average±SEM). Thus, a difference of 4.566 filopodias per tip cell between both groups was seen (CI 95%, P<0.0001; WT: n=27, Sirt3-/-: n=20). 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.

Conclusions : 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 vessel proliferation.

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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