Prevention of inflammation-associated preterm birth by knockdown of the endothelin-1-matrix metalloproteinase-1 pathway.
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.
Wang
Wei
W
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, United States of America.
Yen
Haoting
H
Chen
Chih-Hung
CH
Jasani
Nitesh
N
Soni
Rimabahen
R
Koscica
Karen
K
Reznik
Sandra E
SE
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D005260:Female; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000517:prevention & control*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D007752:Obstetric Labor, Premature; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D047928:Premature Birth / Q000517:prevention & control*; D034622:RNA Interference; D015145:Tocolysis; D014599:Uterus / Q000378:metabolism
D019332:Endothelin-1; D016282:Aspartic Acid Endopeptidases; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; C507081:Mmp13 protein, mouse; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes
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