Increased hydrogen peroxide downregulates soluble guanylate cyclase in the lungs of lambs with persistent pulmonary hypertension of the newborn.
Similar to infants born with persistent pulmonary hypertension of the newborn (PPHN), there is an increase in circulating endothelin-1 (ET-1) and decreased cGMP-mediated vasodilation in an ovine model of PPHN. These abnormalities lead to vasoconstriction and vascular remodeling. Our previous studies have demonstrated that reactive oxygen species (ROS) levels are increased in pulmonary arterial smooth muscle cells (PASMC) exposed to ET-1. Thus the initial objective of this study was to determine whether the development of pulmonary hypertension in utero is associated with elevated production of the ROS hydrogen peroxide (H(2)O(2)) and if this is associated with alterations in antioxidant capacity. Second we wished to determine whether chronic exposure of PASMC isolated from fetal lambs to H(2)O(2) would mimic the decrease in soluble guanylate cyclase expression observed in the ovine model of PPHN. Our results indicate that H(2)O(2) levels are significantly elevated in pulmonary arteries isolated from 136-day-old fetal PPHN lambs (P 0.05). In addition, we determined that catalase and glutathione peroxidase expression and activities remain unchanged. Also, we found that the overnight exposure of fetal PASMC to a H(2)O(2)-generating system resulted in significant decreases in soluble guanylate cyclase expression and nitric oxide (NO)-dependent cGMP generation (P 0.05). Finally, we demonstrated that the addition of the ROS scavenger catalase to isolated pulmonary arteries normalized the vasodilator responses to exogenous NO. As these scavengers had no effect on the vasodilator responses in pulmonary arteries isolated from age-matched control lambs this enhancement appears to be unique to PPHN. Overall our data suggest a role for H(2)O(2) in the abnormal vasodilation associated with the pulmonary arteries of PPHN lambs.
Wedgwood
Stephen
S
Dept. of Pediatrics, Northwestern University, Chicago, Illinois, USA.
Steinhorn
Robin H
RH
Bunderson
Melisa
M
Wilham
Jason
J
Lakshminrusimha
Satyan
S
Brennan
Lisa A
LA
Black
Stephen M
SM
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006162:Guanylate Cyclase; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008168:Lung / Q000201:enzymology* / Q000503:physiopathology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000201:enzymology* / Q000503:physiopathology; D011652:Pulmonary Circulation; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012756:Sheep; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation
D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D006861:Hydrogen Peroxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase