Altered regulation of the ET-1 cascade in lambs with increased pulmonary blood flow and pulmonary hypertension

Stephen M. Black, Janine M. Bekker, Michael J. Johengen, Andrew J. Parry, Scott J. Soifer, Jeffrey R. Fineman

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Plasma concentrations of endothelin-1 (ET-1) are increased in children with congenital heart disease associated with increased pulmonary blood flow. However, the role of ET-1 in the pathophysiology of pulmonary hypertension remains unclear. Preproendothelin-1 gene expression is increased in adults with advanced pulmonary hypertension. To characterize potential early molecular alterations in the ET-1 cascade induced by increased pulmonary blood flow and pulmonary hypertension, fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). RNase protection assays and Western blot analysis were performed on lung tissue prepared from 4-wk-old shunt lambs and age-matched controls. Endothelin-converting enzyme-1 [the enzyme responsible for the production of active ET-1 from big ET-1, mRNA (411%, p < 0.05)] and protein (170%, p < 0.05) were increased in lung tissue prepared from shunt lambs, compared with age-matched controls. Endothelin type A receptor (the receptor that mediates vasoconstriction), mRNA (246%, p < 0.05), and protein (176%, p < 0.05) also were increased in lung tissue prepared from shunt lambs compared with age-matched controls. Conversely, endothelin type B receptor (the receptor that mediates vasodilation), mRNA (46%, p < 0.05), and protein (65%, p < 0.05) were decreased in shunt lambs. Both the mRNA and protein levels for preproendothelin-1 were unchanged. Thus we conclude that increased pulmonary blood flow and pulmonary hypertension induce early alterations in the ET-1 cascade that result in increased ET-1 production, increased ET-1-mediated vasoconstriction, and decreased vasodilation. These early alterations in gene expression may contribute to the development of pulmonary hypertension and its associated enhanced pulmonary vascular reactivity.

Original languageEnglish (US)
Pages (from-to)97-106
Number of pages10
JournalPediatric research
Volume47
Issue number1
DOIs
StatePublished - Jan 2000

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Fingerprint Dive into the research topics of 'Altered regulation of the ET-1 cascade in lambs with increased pulmonary blood flow and pulmonary hypertension'. Together they form a unique fingerprint.

  • Cite this

    Black, S. M., Bekker, J. M., Johengen, M. J., Parry, A. J., Soifer, S. J., & Fineman, J. R. (2000). Altered regulation of the ET-1 cascade in lambs with increased pulmonary blood flow and pulmonary hypertension. Pediatric research, 47(1), 97-106. https://doi.org/10.1203/00006450-200001000-00018