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Decreases in manganese superoxide dismutase expression and activity contribute to oxidative stress in persistent pulmonary hypertension of the newborn.

Abstract
A rapid increase in the synthesis and release of nitric oxide (NO) facilitates the pulmonary vasodilation that occurs during birth-related transition. Alteration of this transition in persistent pulmonary hypertension of the newborn (PPHN) is associated with impaired function of endothelial nitric oxide synthase (eNOS) and an increase in oxidative stress. We investigated the hypothesis that a decrease in expression and activity of mitochondrial localized manganese superoxide dismutase (MnSOD) in pulmonary artery endothelial cells (PAEC) increases oxidative stress and impairs eNOS function in PPHN. We isolated PAEC and pulmonary arteries from fetal lambs with PPHN induced by prenatal ductus arteriosus ligation or sham ligation (control). We investigated MnSOD expression and activity, tyrosine nitration of MnSOD, and mitochondrial O(2)(-) levels in PAEC from control and PPHN lambs. We introduced exogenous MnSOD via an adenoviral vector (ad-MnSOD) transduction into PAEC and pulmonary arteries of PPHN lambs. The effect of ad-MnSOD was investigated on: mitochondrial O(2)(-) levels, MnSOD and eNOS expression and activity, intracellular hydrogen peroxide (H(2)O(2)) levels, and catalase expression in PAEC. MnSOD mRNA and protein levels and activity were decreased and MnSOD tyrosine nitration was increased in PPHN-PAEC. ad-MnSOD transduction of PPHN-PAEC increased its activity two- to threefold, decreased mitochondrial O(2)(-) levels, and increased H(2)O(2) levels and catalase expression. ad-MnSOD transduction improved eNOS expression and function and the relaxation response of PPHN pulmonary arteries. Our observations suggest that decreased MnSOD expression and activity contribute to the endothelial dysfunction observed in PPHN.
AuthorsAdeleye J Afolayan, Annie Eis, Ru-Jeng Teng, Ivane Bakhutashvili, Sushma Kaul, Jonathan M Davis, Girija G Konduri
JournalAmerican journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 303 Issue 10 Pg. L870-9 (Nov 15 2012) ISSN: 1522-1504 [Electronic] United States
PMID22962015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • RNA, Messenger
  • Superoxides
  • Nitric Oxide
  • Hydrogen Peroxide
  • Nitric Oxide Synthase Type III
  • Superoxide Dismutase
Topics
  • Adenoviridae
  • Animals
  • Disease Models, Animal
  • Endothelial Cells (enzymology, pathology)
  • Gene Expression Regulation, Enzymologic
  • Genetic Vectors
  • Humans
  • Hydrogen Peroxide (metabolism)
  • Infant, Newborn
  • Mitochondria (enzymology, genetics, pathology)
  • Nitric Oxide (biosynthesis, genetics)
  • Nitric Oxide Synthase Type III (biosynthesis, genetics)
  • Oxidative Stress
  • Persistent Fetal Circulation Syndrome (enzymology, genetics, pathology, physiopathology)
  • Pulmonary Artery (enzymology, pathology, physiopathology)
  • RNA, Messenger (biosynthesis, genetics)
  • Sheep
  • Superoxide Dismutase (biosynthesis, genetics)
  • Superoxides (metabolism)
  • Transduction, Genetic
  • Vasodilation (genetics)

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