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Nogo-B Receptor Modulates Pulmonary Artery Smooth Muscle Cell Function in Developing Lungs. Am J Respir Cell Mol Biol 2016 06;54(6):892-900

Date

12/15/2015

Pubmed ID

26652754

Pubmed Central ID

PMC4942214

DOI

10.1165/rcmb.2015-0068OC

Abstract

Nogo-B and its receptor (NgBR) are involved in blood vessel growth in developing lungs, but their role in pulmonary artery smooth muscle cell (PASMC) growth is unknown. We hypothesized that NgBR regulates growth of PASMCs by modulating the function of endoplasmic reticulum (ER) and formation of reactive oxygen species (ROS). In utero constriction of the ductus arteriosus created pulmonary hypertension in fetal lambs (hypertensive fetal lamb [HTFL]). PASMCs isolated 8 days after surgery were assessed for the alteration of protein levels by immunoblots and ROS formation by dihydroethidium and Cell ROX deep red fluorescence. NgBR small interfering RNA and plasmid DNA were used to manipulate NgBR levels. Proliferation and wound healing were assessed by cell counts and scratch recovery assay, respectively. Acute ER stress was induced by tunicamycin. Differences of mitogen-activated protein kinase and Akt pathway activation in HTFL versus control PASMCs were evaluated. Results showed that HTFL PASMCs had decreased NgBR levels and increased proliferation, wound healing, ER stress, and ROS formation compared with controls. Knockdown of NgBR in control PASMCs generated a phenotype similar to HTFL, and overexpression in HTFL restored the defective phenotype to control. Decreased NgBR levels were associated with increased ROS formation in HTFL PASMCs. Subsequently, scavenging ROS decreased proliferation and wound healing. Mechanistically, ROS formation decreases NgBR expression, which induces ER stress. This leads to extracellular signal-regulated kinase pathway activation and PASMC phenotype alteration. Our data suggest that decreased NgBR expression in pulmonary hypertension of the newborn contributes to increased PASMC proliferation and oxidative stress, which lead to the pathogenesis of lung injury.

Author List

Tadokoro KS, Rana U, Jing X, Konduri GG, Miao QR, Teng RJ

Authors

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

Animals
Catalase
Cell Movement
Cell Proliferation
Endoplasmic Reticulum Stress
Fetus
Gene Knockdown Techniques
Hypertension, Pulmonary
Lung
Mitogen-Activated Protein Kinases
Myocytes, Smooth Muscle
Phosphorylation
Pulmonary Alveoli
Pulmonary Artery
Reactive Oxygen Species
Receptors, Cell Surface
Sheep
Superoxide Dismutase
Wound Healing
jenkins-FCD Prod-480 9a4deaf152b0b06dd18151814fff2e18f6c05280