Prostaglandin E2 receptor subtype EP2- and EP4-regulated gene expression profiling in human ciliary smooth muscle cells.
Prostanoids are an important class of intraocular pressure (IOP)-lowering antiglaucoma agents that act primarily via increased uveo-scleral aqueous humor outflow through the ciliary body. We have developed two novel PGE(2) analogs that are specific agonists for the PGE(2) receptor subtypes EP2 and EP4, respectively. To identify gene regulatory networks and key players that mediate the physiological effects observed in vivo, we performed genomewide expression studies using human ciliary smooth muscle cells. Quantitative real-time RT-PCR confirmed a largely overlapping gene expression profile subsequent to EP2 and EP4 agonist treatment, with 65 significantly regulated genes identified overall, 5 being specific for the EP2 agonist and 6 specific for the EP4 agonist. We found predicted functional cAMP-response elements in promoter regions of a large fraction of the predominantly upregulated genes, which suggests that the cAMP signaling pathway is the most important intracellular signaling pathway for these agonists in these cells. Several target genes were identified that, as part of complex regulatory networks, are implicated in tissue remodeling processes and osmoregulation (e.g., AREG, LOXL3, BMP2, AQP3) and thus may help elucidate the mechanism of action of these IOP-lowering drugs involving the uveo-scleral outflow path.
Reitmair
Armin
A
Department of Biological Sciences, Allergan Incorporated, Irvine, CA 92612, USA. reitmair_armin@allergan.com
Lambrecht
Nils W G
NW
Yakubov
Iskandar
I
Nieves
Amelia
A
Old
David
D
Donde
Yariv
Y
Dinh
Danny
D
Burk
Robert
R
Sachs
George
G
Im
Wha Bin
WB
Wheeler
Larry
L
D002478:Cells, Cultured; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D046228:Microarray Analysis; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D011465:Prostaglandins, Synthetic / Q000494:pharmacology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054928:Validation Studies as Topic
D011465:Prostaglandins, Synthetic; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype