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D. L. Fleenor, I.-H. Pang, A. F. Clark; Regulation of PAI-1 Protein in Human Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1631. doi: https://doi.org/.
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An increased level of plasminogen activator inhibitor-1 (PAI-1) appears to play a role in a variety of disease states, including cancer, obesity, and diabetes. Elevated PAI-1 levels have also been reported in the aqueous humor of glaucoma patients. Human trabecular meshwork (HTM) cells express PAI-1 protein in vitro. We investigated the signaling mechanisms involved in HTM cell production of PAI-1 protein.
HTM cells were treated with transforming growth factor-beta2 (TGFβ2), a known stimulator of PAI-1 secretion, in the presence or absence of various signal transduction pathway inhibitors. Supernatants from the treated cultures were analyzed by ELISA for total PAI-1 protein content.
Average basal PAI-1 secretion by GTM-3 cells was 33.9 + 1.5 ng/mL/24 h (n = 233). TGFβ2 increased PAI-1 content of GTM-3 cell supernatants in a time and dose-dependent manner; a 24 h treatment with 5 ng/mL TGFβ2, enhanced PAI-1 levels by 12.02 + 0.03 fold. TGFβ2-stimulated PAI-1 levels were significantly (p < 0.05) down-regulated by inhibitors of both canonical (Smad-mediated) and non-canonical (Smad-independent) signal transduction pathways. Overall response varied from complete inhibition by agents such as SB431542 (TGFβ Type 1 receptor inhibitor; 1 µM) and rottlerin (PKCΔ inhibitor; 10 µM) to partial inhibition by SB202190 (p38 MAPK inhibitor; 100 nM), SP600125 (c-Jun N-terminal kinase inhibitor; 1 µM), and various statin agents.
Modulation of PAI-1 protein expression by TGFβ2 is a complex process, involving multiple signaling pathways/mechanisms. Perturbation of one or more of these pathways may provide a novel and viable therapeutic approach to the management of glaucoma.
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