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Joshua Hines, Stephanie Ecker, Bert Glaser, ; Sequential in-office Vitreous aspirations demonstrate that up-regulation of Matrix Metalloproteinases may regulate angiogenesis in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1144.
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The progression from non-proliferative Diabetic Retinopathy (NPDR) to proliferative Diabetic Retinopathy (PDR) has been well documented clinically, but the stimulus of this progression has yet to be elucidated. Recent studies have demonstrated that measuring activated proteins and their receptors in the vitreous correlate with disease activity & treatment response. We therefore compared the vitreous proteome of NPDR eyes to eyes with PDR to determine which biochemical pathways might be involved in the progression of DR.
One hundred (100) in-office vitreous aspirations from 54 eyes (approx. 50-100 µL each) were obtained from patients who presented with either NPDR (42 eyes) or PDR (12 eyes). Each aspiration was taken just prior to the patient receiving intra-vitreal anti-VEGF. All vitreous samples were investigated for 33 proteins using RPPM (Reverse Phase Protein Microarray) Technology as previously described. Each of these proteins was chosen because they represent crucial components of biochemical pathways involved in DR: inflammation, apoptosis, hypoxia and angiogenesis.
4 of 33 measured proteins showed statistically significant differences between NPDR and PDR. These proteins were Matrix Metalloproteinase 9 (MMP-9) [p=.044, AUC=.7078], Matrix Metalloproteinase 14 (MMP-14) [p=.0122, AUC=.7062], Vascular Endothelial Growth Factor 1175 (VEGF R2 Tyr1175) [p=.0088, AUC=.7024], and Bcl-2 thr56[(p=.0083, AUC=.7064]. All four of the same proteins were significantly up-regulated in NPDR versus PDR groups: MMP-9 (48.7%), MMP-14(32.9%), VEGF R2 Tyr1175 (43.1%), & Bcl-2 thr 56 (33.4%). VEGF-A showed some up-regulation but fell short of statistical significance.
Up-regulation of MMP-9, MMP-14, Activated VEGF R2 Tyr1175 and Bcl-2 thr 56 in PDR patients suggests a role in the conversion from NPDR to PDR. Hyperglycemia induced MMP-9 activation stimulates apoptotic activity among pericytes, capillary cells and endothelial cells. It should be noted that studies have implicated these same biochemical markers during the transformation of many non-metastatic to metastatic cancers. This is the first time that human vitreous samples have been sequentially sampled and investigated for proteomic changes along with clinical progression in different subsets of DR patients.
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