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Decreases in manganese superoxide dismutase expression and activity contribute to oxidative stress in persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 2012 Nov 15;303(10):L870-9

Date

09/11/2012

Pubmed ID

22962015

Pubmed Central ID

PMC3517675

DOI

10.1152/ajplung.00098.2012

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.

Author List

Afolayan AJ, Eis A, Teng RJ, Bakhutashvili I, Kaul S, Davis JM, Konduri GG

Authors

Adeleye James Afolayan MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Ru-Jeng Teng MD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenoviridae
Animals
Disease Models, Animal
Endothelial Cells
Gene Expression Regulation, Enzymologic
Genetic Vectors
Humans
Hydrogen Peroxide
Infant, Newborn
Mitochondria
Nitric Oxide
Nitric Oxide Synthase Type III
Oxidative Stress
Persistent Fetal Circulation Syndrome
Pulmonary Artery
RNA, Messenger
Sheep
Superoxide Dismutase
Superoxides
Transduction, Genetic
Vasodilation
jenkins-FCD Prod-400 0f9a74600e4e79798f8fa6f545ea115f3dd948b2