Differential Expression and Localization of ADAMTS Proteinases in Proliferative Diabetic Retinopathy
Ahmed M Abu El-Asrar1,2, Mohd Imtiaz Nawaz1, Eef Allegaert3
1Department of Ophthalmology, College of Medicine, King Saud University, PO Box 245, Riyadh 11411, Saudi Arabia.
Abstract:
We analyzed the expression of ADAMTS proteinases ADAMTS-1, -2, -4, -5 and -13; their activating enzyme MMP-15; and the degradation products of proteoglycan substrates versican and biglycan in an ocular microenvironment of proliferative diabetic retinopathy (PDR) patients. Vitreous samples from PDR and nondiabetic patients, epiretinal fibrovascular membranes from PDR patients, rat retinas, retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied. The levels of ADAMTS proteinases and MMP-15 were increased in the vitreous from PDR patients. Both full-length and cleaved activation/degradation fragments of ADAMTS proteinases were identified. The amounts of versican and biglycan cleavage products were increased in vitreous from PDR patients. ADAMTS proteinases and MMP-15 were localized in endothelial cells, monocytes/macrophages and myofibroblasts in PDR membranes, and ADAMTS-4 was expressed in the highest number of stromal cells. The angiogenic activity of PDR membranes correlated significantly with levels of ADAMTS-1 and -4 cellular expression. ADAMTS proteinases and MMP-15 were expressed in rat retinas. ADAMTS-1 and -5 and MMP-15 levels were increased in diabetic rat retinas. HRMECs and Müller cells constitutively expressed ADAMTS proteinases but not MMP-15. The inhibition of NF-κB significantly attenuated the TNF-α-and-VEGF-induced upregulation of ADAMTS-1 and -4 in a culture medium of HRMECs and Müller cells. In conclusion, ADAMTS proteinases, MMP-15 and versican and biglycan cleavage products were increased in the ocular microenvironment of patients with PDR.
Insights
Levels of ADAMTS proteinases and MMP-15, along with versican and biglycan cleavage products, are elevated in proliferative diabetic retinopathy (PDR). These molecules are implicated in the ocular microenvironment of PDR patients.
Area of Science:
- Ophthalmology
- Molecular Biology
- Biochemistry
Background:
- Proliferative diabetic retinopathy (PDR) is a sight-threatening complication of diabetes.
- The molecular mechanisms driving PDR pathogenesis, particularly involving proteases and their substrates, require further elucidation.
- Understanding these mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the expression of ADAMTS proteinases (ADAMTS-1, -2, -4, -5, -13) and their activator MMP-15.
- To analyze the degradation products of proteoglycan substrates versican and biglycan in the PDR ocular microenvironment.
- To correlate protease expression with angiogenic activity in PDR.
Main Methods:
- Analysis of vitreous samples, epiretinal membranes, rat retinas, Müller glial cells, and human retinal microvascular endothelial cells (HRMECs).
- Quantification of ADAMTS proteinases, MMP-15, and versican/biglycan cleavage products.
- Immunohistochemical localization of proteinases and correlation with angiogenic activity; in vitro studies involving NF-κB inhibition.
Main Results:
- Elevated levels of ADAMTS proteinases and MMP-15 were observed in the vitreous of PDR patients.
- Increased versican and biglycan cleavage products were detected in PDR vitreous.
- ADAMTS proteinases and MMP-15 were localized in cellular components of PDR membranes, with expression correlating to angiogenic activity.
Conclusions:
- ADAMTS proteinases, MMP-15, and their substrate cleavage products are upregulated in the PDR ocular microenvironment.
- These molecules are implicated in the pathogenesis of PDR.
- Targeting these proteases may offer a therapeutic strategy for PDR.
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