Abstract
Prostaglandins ( PGs) have been implicated in the regulation of intraocular pressure ( IOP) by facilitating the remodeling of tissues involved in aqueous humor outflow. A contribution of cyclooxygenase- 2 ( COX- 2)- dependent PGs to this process was emphasized by a recent study showing an impaired COX- 2 expression in the nonpigmented ciliary epithelium ( NPE) of patients with primary open- angle ...
Abstract
Prostaglandins ( PGs) have been implicated in the regulation of intraocular pressure ( IOP) by facilitating the remodeling of tissues involved in aqueous humor outflow. A contribution of cyclooxygenase- 2 ( COX- 2)- dependent PGs to this process was emphasized by a recent study showing an impaired COX- 2 expression in the nonpigmented ciliary epithelium ( NPE) of patients with primary open- angle glaucoma. With the use of human NPE cells ( ODM- 2), the present study therefore investigated the effect of the antiglaucomatous drug latanoprost ( PGF(2 alpha) analog) on the expression of COX- 2 and its association with the induction of matrix metalloproteinases ( MMPs). In NPE cells, latanoprost led to a concentration- and time- dependent increase of COX- 2 mRNA levels. Up- regulation of COX- 2 expression was accompanied by phosphorylations of p38 mitogen- activated protein kinase ( MAPK) and p42/ 44 MAPK and was abrogated by specific inhibitors of both pathways. PGE(2) formation by latanoprost was abolished by the selective COX- 2 inhibitor NS- 398 and by the F- prostaglandin receptor antagonist AL- 8810. Moreover, latanoprost led to a delayed up- regulation of MMP- 1 mRNA, whereas the expression of MMP- 2, MMP- 9, TIMP- 1, and TIMP- 2 remained unchanged. Latanoprost- induced MMP- 1 mRNA and protein expression was abolished by NS- 398 and by COX- 2- silencing small- interfering RNA. In line with this finding, MMP- 1 expression was also induced by PGE2, a major COX- 2 product. As a whole, our results show that MMP- 1 expression by latanoprost requires prior up- regulation of COX- 2. Induction of COX- 2- and subsequent MMP- 1 expression in the NPE may represent a potential mechanism underlying the IOP- lowering and antiglaucomatous action of latanoprost.
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