Oxidative and nitrosative stress in pediatric pulmonary hypertension: Roles of endothelin-1 and nitric oxide

Stephen M. Black, Jeffrey R. Fineman

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

An increasing number of studies implicate oxidative stress in the development of endothelial dysfunction and the pathogenesis of cardiovascular disease. Further, this oxidative stress has been shown to be associated with alterations in both the endothelin-1 (ET-1) and nitric oxide (NO) signaling pathways such that bioavailable NO is decreased and ET-1 signaling is potentiated. However, recent data, from our groups and others, have shown that oxidative stress, ET-1, and NO are co-regulated in a complex fashion that appears to be dependent on the cellular levels of each species. Thus, when ROS levels are transiently elevated, NO signaling is potentiated through transcriptional, post-transcriptional, and post-translational mechanisms. However, in pediatric pulmonary hypertensive disorders, when reactive oxygen species (ROS) increases are sustained by ET-1 mediated activation of smooth muscle cell ETA subtype receptors, NOS gene expression and NO signaling are reduced. Further, increases in oxidative stress can stimulate both the expression of the ET-1 gene and the secretion of the ET-1 peptide. Finally, the addition of exogenous NO, and increasingly utilized therapy for pulmonary hypertension, can also lead to increases ROS generation via the activation of ROS generating enzymes and through the induction of mitochondrial dysfunction. Thus, this manuscript will review the available data regarding the interaction of oxidative and nitrosative stress, endothelial dysfunction, and its role in the pathophysiology of pediatric pulmonary hypertension. In addition, we will suggest avenues of both basic and clinical research that will be important to develop novel pulmonary hypertension treatment and prevention strategies, and resolve some of the remaining clinical issues regarding the use of NO augmentation.

Original languageEnglish (US)
Pages (from-to)308-316
Number of pages9
JournalVascular Pharmacology
Volume45
Issue number5
DOIs
StatePublished - Nov 1 2006

Keywords

  • Cell signaling
  • Gene expression
  • Nitrosylation
  • Pulmonary hypertension
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

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