The endothelin-converting enzyme-1/endothelin-1 pathway plays a critical role in inflammation-associated premature delivery in a mouse model

Wei Wang, Hauting Yen, Chih Hung Chen, Rimabahen Soni, Nitesh Jasani, Georges Sylvestre, Sandra E. Reznik

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1077-1084
Number of pages8
JournalAmerican Journal of Pathology
Volume173
Issue number4
DOIs
StatePublished - Oct 2008
Externally publishedYes

Fingerprint

Endothelin-1
Inflammation
RNA Interference
Endothelin A Receptors
Premature Birth
Enzyme Inhibitors
Hydrodynamics
Transfection
Smooth Muscle
Lipopolysaccharides
Fetus
Parturition
Cytokines
Morbidity
Control Groups
Endothelin-Converting Enzymes
Infection
Therapeutics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

The endothelin-converting enzyme-1/endothelin-1 pathway plays a critical role in inflammation-associated premature delivery in a mouse model. / Wang, Wei; Yen, Hauting; Chen, Chih Hung; Soni, Rimabahen; Jasani, Nitesh; Sylvestre, Georges; Reznik, Sandra E.

In: American Journal of Pathology, Vol. 173, No. 4, 10.2008, p. 1077-1084.

Research output: Contribution to journalArticle

Wang, Wei ; Yen, Hauting ; Chen, Chih Hung ; Soni, Rimabahen ; Jasani, Nitesh ; Sylvestre, Georges ; Reznik, Sandra E. / The endothelin-converting enzyme-1/endothelin-1 pathway plays a critical role in inflammation-associated premature delivery in a mouse model. In: American Journal of Pathology. 2008 ; Vol. 173, No. 4. pp. 1077-1084.
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