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MILYANG KIM, JINA SHIN, KYUNGRIM SUNG; Statins regulate MMP-2 and MMP-9 secretion and activation in human ONH astrocytes.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6145.
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Although stains have shown a beneficial effect on glaucoma, the mechanism of statin action is poorly understood. MMPs are metalloproteases involved in extracellular matrix (ECM) remodeling which leads to optic nerve damage. We hypothesized that stains downregulate MMP-2 and MMP-9 (Matrix Metalloproteinase) secretion and their activation which prevents glaucomatous ECM remodeling.
Optic nerve head (ONH) was isolated from human donors with no history of ocular disease and primary astrocytes were cultured from it. To examine MMPs expression, serum starved astrocytes were treated with TGF-β2 at various concentrations for 24 hours. Conditioned media was subjected to western blotting for MMP-2 and MMP-9. To test statins effect on MMPs secretion, astrocytes were pretreated with statins (simvastatin, lovastatin, and atorvastatin at 5μg/ml) for 1 hour. To test MMPs activation, serum starved astrocytes were treated with statin for 1 hour followed by TGF-β2 for 24 hours. Conditioned media from astrocyte culture was run on gel and stained for zymography.
TGF-β2 treatment simulates glaucomatous condition in ONH (optic nerve head) astrocyte. TGF-β2 induced MMP-2 and MMP-9 secretion in human ONH astrocyte maximizing at 5ng/ml concentration. When astrocytes were pretreated with statins, TGF-β2-mediated MMP-2 and MMP-9 secretion was suppressed by all three statins, simvastatin, lovastatin and atorvastatin. Regulation of MMP activation by statins was studied using zymography. The MMPs become active when pro-peptide domain is cleaved off. We observed that TGF-β2 induced not only proMMPs but also active MMPs levels in astrocyte media. Pretreatment with statins effectively reduced levels of both pro and active MMPs.
Consistent with our hypothesis, statins were able to suppress TGF-β2-mediated MMP-2 and MMP-9 secretion and their activation in human ONH astrocytes. The question on how stains regulate MMPs secretion and activation needs to be answered by further study.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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