The endothelin-converting enzyme-1/endothelin-1 pathway plays a critical role in inflammation-associated premature delivery in a mouse model.
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.
Wang
Wei
W
Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439, USA.
Yen
Haoting
H
Yen
Hauting
H
Chen
Chih-Hung
CH
Soni
Rimabahen
R
Jasani
Nitesh
N
Sylvestre
Georges
G
Reznik
Sandra E
SE
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
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)
Obstet Gynecol Surv. 2000 Oct;55(10):650-60
11023206
Am J Obstet Gynecol. 2007 Jun;196(6):551.e1-3
17547891
Am J Obstet Gynecol. 1994 Dec;171(6):1660-7
7802084
Am J Pathol. 2003 Nov;163(5):2103-11
14578208
Can J Physiol Pharmacol. 2008 Aug;86(8):571-5
18758506
Am J Obstet Gynecol. 1992 Dec;167(6):1583-8
1471670
Am J Obstet Gynecol. 1992 May;166(5):1576-87
1595815
Br Med J. 1976 Oct 23;2(6042):965-8
974709
Development. 1998 Mar;125(5):825-36
9449665
Am J Reprod Immunol. 1992 Apr-May;27(3-4):117-23
1418402
Am J Obstet Gynecol. 1999 Aug;181(2):359-66
10454683
Gynecol Obstet Invest. 1993;36(3):166-71
8244191
Am J Obstet Gynecol. 1994 May;170(5 Pt 1):1467-75
8178889
Biol Reprod. 2002 Aug;67(2):668-73
12135912
Placenta. 1998 Nov;19(8):625-30
9859867
Pharmacol Ther. 2006 Jun;110(3):386-414
16219361
Nat Genet. 2002 Sep;32(1):107-8
12145662
Bioessays. 2001 Mar;23(3):261-9
11223883
Biochem Pharmacol. 1996 Jan 26;51(2):91-102
8615890
Biol Reprod. 2003 Dec;69(6):1957-63
12904319
N Engl J Med. 2000 May 18;342(20):1500-7
10816189
Nature. 1988 Mar 31;332(6163):411-5
2451132
J Soc Gynecol Investig. 1996 Nov-Dec;3(6):328-35
8923417
Mol Pharmacol. 1999 May;55(5):902-9
10220569
Am J Obstet Gynecol. 1999 Feb;180(2 Pt 1):429-34
9988814
Reprod Sci. 2008 Apr;15(4):420-4
18497349
Biol Reprod. 1994 Oct;51(4):640-5
7819444
N Engl J Med. 2007 Aug 2;357(5):477-87
17671256
J Reprod Med. 1999 Feb;44(2):115-21
10853442
Reprod Sci. 2008 Feb;15(2):108-9
18276947
Am J Obstet Gynecol. 2004 Feb;190(2):528-31
14981401