September 2014
Volume 55, Issue 9
Research Highlight  |   September 2014
Sirt1, A Negative Regulator of Matrix Metalloproteinase-9 in Diabetic Retinopathy
Investigative Ophthalmology & Visual Science September 2014, Vol.55, 5661. doi:
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      Mojca Globočnik Petrovič; Sirt1, A Negative Regulator of Matrix Metalloproteinase-9 in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(9):5661.

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

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Diabetic retinopathy is characterized by increased vascular permeability, hemostatic abnormalities, endothelial dysfunction, increased tissue ischemia, and neoangiogenesis. 1 Several candidate genes have been implicated in the pathogenesis of diabetic retinopathy via complex interactions of environmental, genetic, and epigenetic factors. 2 Epigenetic changes occur without alterations in the DNA sequence and can affect gene transcription in response to environmental changes. Transition from the active to the inactive state of chromatin is the central mechanism of gene regulation, and this is defined as an epigenetic factor. Several pathways may be involved in the epigenetic regulation, such as DNA methylation, histone acetylation, and microRNAs. 3  
A few years ago it was demonstrated that the activated matrix metalloproteinase (MMP)-9 has an important role in the pathogenesis of diabetic retinopathy by affecting apoptotic machinery in mitochondria and increasing oxidative stress. 4 Moreover, increased oxidative stress markers were demonstrated in diabetic retinopathy. 4,5 In diabetes, the binding of p65 with MMP-9 promoter regulates retinal MMP-9. 4 In this edition of IOVS, Kowluru et al. 6 asked the question whether and how oxidative stress inhibition/activation via p65 acetylation affects MMP-9 activity in retinal endothelial cells. In high glucose medium, increased acetylation of p65 was demonstrated, whereas infusion of Sirt1 activator (resveratrol) in high glucose medium prevented the increase in the acetylation of p65. Importantly, infusion of resveratrol in normal glucose medium had no effect on p65 acetylation and MMP-9 activity, demonstrating the importance of epigenetics. 6  
Kowluru et al. 6 have demonstrated that in diabetes, increased oxidative stress inhibits Sirt1, resulting in hyperacetylated p65 and binding of p65 with MMP-9, leading to mitochondrial damage in retinal endothelial cells. In contrast, the activation of Sirt1 by resveratrol inhibited MMP-9 and protected the mitochondrial damage in retinal endothelial cells. 6 In the future, the regulation of Sir1 with pharmaceutical/nutritional means could serve as a potential target to prevent or at least delay the development of diabetic retinopathy. 
Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes . 2005; 54: 1615–1625. [CrossRef] [PubMed]
Petrovič D. Candidate genes for proliferative diabetic retinopathy. Biomed Res Int . 2013; 2013: 540416. [PubMed]
Reddy MA Natarajan R. Epigenetic mechanisms in diabetic vascular complications. Cardiovasc Res . 2011; 90: 421–429. [CrossRef] [PubMed]
Kowluru RA Mohammad G dos Santos JM Zhong Q. Abrogation of MMP-9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damage. Diabetes . 2011; 60: 3023–3033. [CrossRef] [PubMed]
Cilenšek I Mankoč S Petrovič MG Petrovič D. GSTT1 null genotype is a risk factor for diabetic retinopathy in Caucasians with type 2 diabetes, whereas GSTM1 null genotype might confer protection against retinopathy. Dis Markers . 2012; 32: 93–99. [CrossRef] [PubMed]
Kowluru RA Santos JM Zhong Q. Sirt1, a negative regulator of matrix metalloproteinase-9 in diabetic retinopathy. Invest Ophthalmol Vis Sci . 2014; 55: 5653–5660. [CrossRef] [PubMed]

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