title: Targeting prostaglandin E2 receptors as an alternative strategy to block cyclooxygenase-2-dependent extracellular matrix-induced matrix metalloproteinase-9 expression by macrophages.
abstract: COX-2-dependent prostaglandin (PG) E2 synthesis regulates macrophage MMP expression, which is thought to destabilize atherosclerotic plaques. However, the administration of selective COX-2 inhibitors paradoxically increases the frequency of adverse cardiovascular events potentially through the loss of anti-inflammatory prostanoids and/or disturbance in the balance of pro- and anti-thrombotic prostanoids. To avoid these collateral effects of COX-2 inhibition, a strategy to identify and block specific prostanoid-receptor interactions may be required. We previously reported that macrophage engagement of vascular extracellular matrix (ECM) triggers proteinase expression through a MAPKerk1/2-dependent increase in COX-2 expression and PGE2 synthesis. Here we demonstrate that elicited macrophages express the PGE2 receptors EP1-4. When plated on ECM, their expression of EP2 and EP4, receptors linked to PGE2-induced activation of adenylyl cyclase, is strongly stimulated. Forskolin and dibutryl cyclic-AMP stimulate macrophage matrix metalloproteinase (MMP)-9 expression in a dose-dependent manner. However, an EP2 agonist (butaprost) has no effect on MMP-9 expression, and macrophages from EP2 null mice exhibited enhanced COX-2 and MMP-9 expression when plated on ECM. In contrast, the EP4 agonist (PGE1-OH) stimulated macrophage MMP-9 expression, which was inhibited by the EP4 antagonist ONO-AE3-208. When compared with COX-2 silencing by small interfering RNA or inhibition by celecoxib, the EP4 antagonist was as effective in inhibiting ECM-induced proteinase expression. In addition, ECM-induced MMP-9 expression was blocked in macrophages in which EP4 was silenced by small interfering RNA. Thus, COX-2-dependent ECM-induced proteinase expression is effectively blocked by selective inhibition of EP4, a member of the PGE2 family of receptors.
authors.affiliation: Department of Pathology and Laboratory Medicine, Vascular Biology Center, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Pavlovic
authors.forename: Baoheng
authors.initials: B
authors.lastname: Du
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakamoto
authors.forename: K M Faisal
authors.initials: KM
authors.lastname: Khan
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Natarajan
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
authors.forename: Domenick J
authors.initials: DJ
authors.lastname: Falcone
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003994:Bucladesine / Q000378:metabolism; D000068579:Celecoxib; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005109:Extracellular Matrix / Q000201:enzymology* / Q000378:metabolism; D020868:Gene Silencing; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D009841:Oligonucleotides / Q000737:chemistry; D010537:Peritoneum / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D009281:Naphthalenes; D009841:Oligonucleotides; D010654:Phenylbutyrates; D011720:Pyrazoles; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; D005576:Colforsin; D003994:Bucladesine; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; D000068579:Celecoxib