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Meihua Ju, Shaday Michan, Christian G Hurst, Zhenghao Cui, Lucy P Evans, Lois Smith, Jing Chen; Over-expression of sirtuins does not protect against retinal neovascularization in a mouse model of oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5399.
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Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. The interaction between retinal neurons and vessels play an important role in the pathogenesis of retinopathy. Sirtuins are a group of protein deacetylases whose activities are dependent on nicotinamide adenine dinucleotide (NAD+) as a co-activator. Accumulating studies support that sirtuins play major roles in many neurodegenerative diseases. Our lab has previously found that Sirtuin 1 is essential in mediating neurovascular crosstalk and regulating vascular regeneration in a mouse model of oxygen-induced ischemic retinopathy (OIR), as depletion of Sirtuin 1 in retinal neurons worsens retinopathy. In this study, we investigated whether over-expression of Sirtuin 1, Sirtuin 2 and Sirtuin 5 in retinal neurons and vessels may protect against retinopathy.
Over-expression of Sirtuin 1, 2 or 5 in retinal neurons is achieved by crossing Sirtuin 1, 2 or 5 over-expressing flox mice with Nestin-Cre mice, while endothelial specific over-expression of the sirtuins are achieved by crossing Sirtuin 1, 2 or 5 over-expressing flox mice with Tie2-Cre mice. Neonatal mice with their nursing mother were exposed to 75% oxygen from P7 to P12 then raised in room air until P17 to induce retinopathy. Mice were collected at various ages during development of OIR. Retinae were stained with Alexa Fluor 594 conjugated Griffonia Simplicifolia Isolectin B4 to visualize blood vessels. Whole-mounted retinas were imaged at 5x magnification. Vascular loss and neovascularization in OIR were quantified using Adobe Photoshop or Image J software.
There was no significant difference in vaso-obliteration or pathologic neovascularization between the Nestin-Cre Sirtuin mice and the Cre control mice or Flox control mice. Similarly, over-expression of Sirtuin 1, 2 or 5 in Tie-2 expressing vascular endothelial cells and monocyte/macrophages does not show an impact on retinal vessels in OIR.
Although endogenous Sirtuins are important as stress-induced protectors in retinopathy, over-expression of Sirtuin 1, 2 or 5 in retinal neurons or vessels does not provide additional protection against retinopathy in mice.
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