Pediatric pulmonary hypertension: Roles of endothelin-1 and nitric oxide.
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 ET(A) 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. Thus, this manuscript will review the available data regarding the interaction of NO, ET-1, and ROS in the endothelial dysfunction 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.
Black
Stephen M
SM
Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USA. sblack@mcg.edu
Kumar
Sanjiv
S
Wiseman
Dean
D
Ravi
Kandasamy
K
Wedgwood
Stephen
S
Ryzhov
Victor
V
Fineman
Jeffrey R
JR
D002648:Child; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
D019332:Endothelin-1; D017382:Reactive Oxygen Species; D009569:Nitric Oxide