Interaction of endothelial nitric oxide synthase with mitochondria regulates oxidative stress and function in fetal pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol 2015 Nov 01;309(9):L1009-17
Date
09/01/2015Pubmed ID
26320159Pubmed Central ID
PMC4628983DOI
10.1152/ajplung.00386.2014Scopus ID
2-s2.0-84946434013 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
An increase in oxygen tension at birth is one of the key signals that initiate pulmonary vasodilation in the fetal lung. We investigated the hypothesis that targeting endothelial nitric oxide synthase (eNOS) to the mitochondrial outer membrane regulates reactive oxygen species (ROS) formation in the fetal pulmonary artery endothelial cells (PAEC) during this transition. We isolated PAEC and pulmonary arteries from 137-day gestation fetal lambs (term = 144 days). We exposed PAEC to a simulated transition from fetal to (3% O2) to normoxic (21%) or hyperoxic (95% O2) postnatal Po2 or to the nitric oxide synthase (NOS) agonist ATP. We assessed the effect of O2 and ATP on eNOS interactions with the mitochondrial outer membrane protein porin and with the chaperone hsp90. We also investigated the effect of decoy peptides that blocked eNOS interactions with porin or hsp90 on PAEC angiogenesis and vasodilator function of pulmonary arteries. Transition of fetal PAEC from 3 to 21% O2 but not to 95% O2 or exposure to ATP increased eNOS association with hsp90 and porin. Decoy peptides that blocked eNOS interactions decreased NO release, increased O2 consumption and mitochondrial ROS levels, and impaired PAEC angiogenesis. Decoy peptides also inhibited the relaxation responses of pulmonary artery rings and dilation of resistance size pulmonary arteries to ATP. The mitochondrial-antioxidant mito-ubiquinone restored the response to ATP in decoy peptide-treated pulmonary arteries. These data indicate that targeting eNOS to mitochondria decreases endothelial oxidative stress and facilitates vasodilation in fetal pulmonary circulation at birth.
Author List
Konduri GG, Afolayan AJ, Eis A, Pritchard KA Jr, Teng RJAuthors
Adeleye James Afolayan MD Associate Professor in the Pediatrics department at Medical College of WisconsinGirija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Ru-Jeng Teng MD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCells, Cultured
Endothelial Cells
Fetus
HSP90 Heat-Shock Proteins
Mitochondria
Nitric Oxide
Nitric Oxide Synthase Type III
Oxidative Stress
Oxygen
Pulmonary Artery
Sheep
Vasodilation