title: The endothelin-converting enzyme-1/endothelin-1 pathway plays a critical role in inflammation-associated premature delivery in a mouse model.
abstract: Premature delivery occurs in 12% of all births and accounts for nearly half of long-term morbidity. Current therapeutic approaches to preterm delivery are ineffective and present serious risks to both mother and fetus. The single most common cause of preterm birth is infection. Previous in vitro investigations have shown that endothelin-1 (ET-1) is induced by inflammatory cytokines and that it increases myometrial smooth muscle tone. Furthermore, we have previously shown that both the endothelin-converting enzyme-1 (ECE-1) inhibitor, phosphoramidon, as well as a novel ET-1 receptor A antagonist synthesized by our group, control premature delivery in a mouse model of inflammation-associated preterm delivery. In the current work, we show that levels of both ET-1 and ECE-1 are increased in gestational tissues in E16.5 mice induced to deliver prematurely after lipopolysaccharide administration. We also show that premature delivery is controlled by treatment with the selective endothelin receptor A antagonist BQ-123 in a dose-dependent manner. Finally, we show here for the first time that premature delivery can be controlled using RNA silencing, by hydrodynamic transfection of E15 mice with ECE-1 RNAi. Taken together, these data support a critical role for the ECE-1/ET-1 system in inflammation-associated premature delivery. The ability to control premature delivery by antagonizing or silencing the ECE-1/ET-1 system offers a novel approach to an unmet clinical need.
authors.affiliation: Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Haoting
authors.initials: H
authors.lastname: Yen
authors.forename: Hauting
authors.initials: H
authors.lastname: Yen
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Rimabahen
authors.initials: R
authors.lastname: Soni
authors.forename: Nitesh
authors.initials: N
authors.lastname: Jasani
authors.forename: Georges
authors.initials: G
authors.lastname: Sylvestre
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Reznik
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D007752:Obstetric Labor, Premature / Q000201:enzymology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy; D047928:Premature Birth / Q000201:enzymology*; D034741:RNA, Small Interfering / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D008070:Lipopolysaccharides; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
references.citation: Obstet Gynecol Surv. 2000 Oct;55(10):650-60
references.pmid: 11023206
references.citation: Am J Obstet Gynecol. 2007 Jun;196(6):551.e1-3
references.pmid: 17547891
references.citation: Am J Obstet Gynecol. 1994 Dec;171(6):1660-7
references.pmid: 7802084
references.citation: Am J Pathol. 2003 Nov;163(5):2103-11
references.pmid: 14578208
references.citation: Can J Physiol Pharmacol. 2008 Aug;86(8):571-5
references.pmid: 18758506
references.citation: Am J Obstet Gynecol. 1992 Dec;167(6):1583-8
references.pmid: 1471670
references.citation: Am J Obstet Gynecol. 1992 May;166(5):1576-87
references.pmid: 1595815
references.citation: Br Med J. 1976 Oct 23;2(6042):965-8
references.pmid: 974709
references.citation: Development. 1998 Mar;125(5):825-36
references.pmid: 9449665
references.citation: Am J Reprod Immunol. 1992 Apr-May;27(3-4):117-23
references.pmid: 1418402
references.citation: Am J Obstet Gynecol. 1999 Aug;181(2):359-66
references.pmid: 10454683
references.citation: Gynecol Obstet Invest. 1993;36(3):166-71
references.pmid: 8244191
references.citation: Am J Obstet Gynecol. 1994 May;170(5 Pt 1):1467-75
references.pmid: 8178889
references.citation: Biol Reprod. 2002 Aug;67(2):668-73
references.pmid: 12135912
references.citation: Placenta. 1998 Nov;19(8):625-30
references.pmid: 9859867
references.citation: Pharmacol Ther. 2006 Jun;110(3):386-414
references.pmid: 16219361
references.citation: Nat Genet. 2002 Sep;32(1):107-8
references.pmid: 12145662
references.citation: Bioessays. 2001 Mar;23(3):261-9
references.pmid: 11223883
references.citation: Biochem Pharmacol. 1996 Jan 26;51(2):91-102
references.pmid: 8615890
references.citation: Biol Reprod. 2003 Dec;69(6):1957-63
references.pmid: 12904319
references.citation: N Engl J Med. 2000 May 18;342(20):1500-7
references.pmid: 10816189
references.citation: Nature. 1988 Mar 31;332(6163):411-5
references.pmid: 2451132
references.citation: J Soc Gynecol Investig. 1996 Nov-Dec;3(6):328-35
references.pmid: 8923417
references.citation: Mol Pharmacol. 1999 May;55(5):902-9
references.pmid: 10220569
references.citation: Am J Obstet Gynecol. 1999 Feb;180(2 Pt 1):429-34
references.pmid: 9988814
references.citation: Reprod Sci. 2008 Apr;15(4):420-4
references.pmid: 18497349
references.citation: Biol Reprod. 1994 Oct;51(4):640-5
references.pmid: 7819444
references.citation: N Engl J Med. 2007 Aug 2;357(5):477-87
references.pmid: 17671256
references.citation: J Reprod Med. 1999 Feb;44(2):115-21
references.pmid: 10853442
references.citation: Reprod Sci. 2008 Feb;15(2):108-9
references.pmid: 18276947
references.citation: Am J Obstet Gynecol. 2004 Feb;190(2):528-31
references.pmid: 14981401