ABSTRACT
Premature delivery occurs in 12% of all births, accounts for nearly half of neonatal morbidity and is increasing in frequency. Current therapeutic approaches to preterm delivery are ineffective and present serious risks to both the mother and fetus. Although there are multiple factors that contribute to the etiology of preterm birth, the single most common cause is infection. Recently, using cDNA microarray analysis of human placental tissue, we demonstrated that human placental matrix metalloproteinase-1 (MMP-1) is upregulated during labor. In a separate line of investigation, we have shown that blockade of endothelin-1 (ET-1) action through the use of an endothelin-converting enzyme-1 (ECE-1) inhibitor, an established commercially available endothelin receptor antagonist or a novel quinolone-derived endothelin receptor antagonist synthesized by our group also prevents preterm labor and delivery in a mouse model. We have now shown that induction of preterm labor with lipopolysaccharide in our mouse model is associated with increased levels of MMP-1. Furthermore, we showed that silencing the ECE-1/ET-1 pathway by using ECE-1 RNA interference prevents both the onset of preterm labor and upregulation of MMP-1. The data indicate that ET-1 and MMP-1 act in the same molecular pathway in preterm labor.
Subject(s)
Aspartic Acid Endopeptidases/metabolism , Inflammation/prevention & control , Metalloendopeptidases/metabolism , Premature Birth/prevention & control , RNA Interference , Animals , Aspartic Acid Endopeptidases/antagonists & inhibitors , Endothelin-1/antagonists & inhibitors , Endothelin-1/metabolism , Endothelin-Converting Enzymes , Female , Gene Knockdown Techniques , Matrix Metalloproteinase 13/metabolism , Metalloendopeptidases/antagonists & inhibitors , Mice , Mice, Inbred C57BL , Models, Animal , Obstetric Labor, Premature , Placenta/metabolism , Pregnancy , Tocolysis , Uterus/metabolismABSTRACT
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.
