Abstract:
PURPOSE:To test the effect of stimulators of activator protein (AP)-1, on expression of stromelysin (MMP-3) in human TM cells and on aqueous outflow in perfused human anterior segments. METHODS:Change in MMP-3 expression was determined by immunoassay of proMMP-3 levels in the media of cultured human TM cells. Anterior segments of human donor eyes with or without glaucoma were perfused with vehicle or the AP-1 stimulator tert-butylhydroquinone (tBHQ). The outflow rates or intraocular pressure (IOP), and proMMP-3 levels in the perfusate were monitored. RESULTS:AP-1 stimulators, such as beta-naphthoflavone, 3-methylcholanthrene, and tBHQ, significantly upregulated (2-4-fold) TM cell expression of MMP-3. The stimulatory effect of tBHQ was concentration dependent, with an EC(50) of approximately 3 micro M, and was blocked by concomitant treatment with 100 nM SR11302, which sequesters AP-1. When nonglaucomatous human eyes were perfused with tBHQ (10 micro M), both outflow rates and perfusate proMMP-3 level increased significantly within the first 24 hours. The outflow effect of tBHQ was suppressed when SR11302 (100 nM) was added in the perfusate. tBHQ also lowered the IOP by more than 40% in perfused glaucomatous eyes. CONCLUSIONS:An AP-1 activator, tBHQ, upregulated expression of MMP-3 in cultured human TM cells and perfused human eyes and enhanced outflow ex vivo. These effects were blocked by sequestering AP-1, suggesting that activation of AP-1 can lead to increased MMP-3 production in the TM, which in turn improves outflow facility. This unique mechanism may provide a novel therapy for glaucoma.
journal_name
Invest Ophthalmol Vis Scijournal_title
Investigative ophthalmology & visual scienceauthors
Pang IH,Fleenor DL,Hellberg PE,Stropki K,McCartney MD,Clark AFdoi
10.1167/iovs.02-0758keywords:
subject
Has Abstractpub_date
2003-08-01 00:00:00pages
3502-10issue
8eissn
0146-0404issn
1552-5783journal_volume
44pub_type
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