title: PGE2 reduces MMP-14 and increases plasminogen activator inhibitor-1 in cardiac fibroblasts.
abstract: Prostaglandin E2 (PGE2) is elevated during cardiac injury and we have previously shown that mice lacking the PGE2 EP4 receptor display dilated cardiomyopathy (DCM) with increased expression of the membrane type matrix metalloproteinase, MMP-14. We thus hypothesized that PGE2 regulates expression of MMP-14 and also affects fibroblast migration. Primary cultures of neonatal rat ventricular fibroblasts (NVFs) were used to test the effects of PGE2. Gene and protein expression was assessed by real time RT-PCR and Western blot, MMP activity was determined by zymography and migration of NVF was assessed by motility in a transwell system. PGE2 reduced expression of MMP-14 and these effects were antagonized by an EP4 antagonist. An EP4 agonist mimicked the effect of PGE2. PGE2 also increased mRNA and protein levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of MMP activation. However, PGE2-stimulation of PAI-1 was mediated by the EP1/EP3 receptor and not EP4. Migration of NVF was assessed by motility in a transwell system. Treatment of NVFs with PGE2 reduced the number of cells migrating toward 10% FCS. Treatment with the EP2 agonist also reduced migration but did not affect MMP-14 expression or PAI-1. Our results suggest that PGE2 utilizes different receptors and mechanisms to ultimately decrease MMP expression and NVF migration.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, United States.
authors.forename: Kamal M
authors.initials: KM
authors.lastname: Kassem
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, United States.
authors.forename: Margarette H
authors.initials: MH
authors.lastname: Clevenger
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Szandzik
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Peterson
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, United States. Electronic address: phardin1@hfhs.org.
authors.forename: Pamela
authors.initials: P
authors.lastname: Harding
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000201:enzymology / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008738:Methyl Ethers / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D008738:Methyl Ethers; D009281:Naphthalenes; C461399:ONO-AE1-329; D010654:Phenylbutyrates; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D058309:Receptors, Prostaglandin E, EP4 Subtype; C016767:sulprostone; D053511:Matrix Metalloproteinase 14; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone
keywords: EP receptors; Fibroblasts; Matrix metalloproteinase; Migration; Plasminogen activator inhibitor-1; Prostaglandin E2