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Matrix metalloproteinases are down-regulated in rat lenses exposed to oxidative stress
Molykutty John1, Cynthia Jaworski, Zhengguang Chen
1Section of Molecular Therapeutics, National Eye Institute, National Institutes of Health, Building 7, Room 202, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Abstract:
Matrix metalloproteinases are important biological effectors of tissue remodelling. Increased MMP expression occurs during injury, inflammation, cellular transformation, and oxidative stress. Oxidative stress in the lens, a causal factor in cataractogenesis, has been shown to induce MMP secretion. The objective of this study was to assess the expression of MMPs and their regulators in an oxidative stress model of cataract, where epithelial cell death and cortical fibre cell swelling occurs in rat lenses after exposure to riboflavin, oxygen, and light. Two time points (4 and 7 hr of exposure) were chosen in order to compare transparent lenses with partially opaque lenses. MMP activity, protein, and mRNA levels were measured. The results show that MMP-2, MMP-9, MT1-MMP, and MT3-MMP are down-regulated by oxidative stress and that the down-regulation is most likely due to reduced gene transcription. In contrast, genes for catalase, glutathione peroxidase, and GAPDH are essentially unaffected, while beta-actin mRNA and protein levels are markedly increased at both time points. The down-regulation of MMPs occurs in lenses still seemingly transparent after 4 hr of exposure, indicating that reduced MMP activity is a relatively early response to the oxidative stress. Moreover, in our model system, MMP inhibition, not induction, is associated with cataractogenesis.
Insights
Oxidative stress down-regulates matrix metalloproteinases (MMPs) in the eye, a key early event in cataract formation. This MMP inhibition, not induction, is linked to cataract development.
Area of Science:
- Ophthalmology
- Molecular Biology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) are crucial for tissue remodeling.
- Increased MMP expression is linked to injury, inflammation, and oxidative stress.
- Oxidative stress in the lens is a known factor in cataractogenesis, potentially inducing MMP secretion.
Purpose of the Study:
- To investigate the expression of MMPs and their regulators in an oxidative stress model of cataract.
- To analyze changes in MMPs in rat lenses exposed to riboflavin, oxygen, and light at 4 and 7 hours.
- To correlate MMP activity with early stages of cataract development.
Main Methods:
- Induction of oxidative stress in rat lenses using riboflavin, oxygen, and light.
- Measurement of MMP activity, protein, and mRNA levels at 4 and 7 hours post-exposure.
- Analysis of gene expression for MMPs, catalase, glutathione peroxidase, GAPDH, and beta-actin.
Main Results:
- MMP-2, MMP-9, MT1-MMP, and MT3-MMP expression were down-regulated by oxidative stress, primarily due to reduced gene transcription.
- Genes for catalase, glutathione peroxidase, and GAPDH remained largely unaffected.
- Beta-actin mRNA and protein levels significantly increased.
- MMP down-regulation was observed in lenses still transparent at 4 hours, indicating an early response.
Conclusions:
- Oxidative stress leads to the down-regulation of specific MMPs in the lens.
- This down-regulation is an early event in the cataractogenesis process.
- MMP inhibition, rather than induction, is associated with cataract development in this model.
