Targeting pulmonary endothelial hemoglobin a improves nitric oxide signaling and reverses pulmonary artery endothelial dysfunction

Roger A. Alvarez, Megan P. Miller, Scott A. Hahn, Joseph C. Galley, Eileen Bauer, Timothy Bachman, Jian Hu, John Sembrat, Dmitry Goncharov, Ana L. Mora, Mauricio Rojas, Elena Goncharova, Adam C. Straub

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Pulmonary hypertension is characterized by pulmonary endothelial dysfunction. Previous work showed that systemic artery endothelial cells (ECs) express hemoglobin (Hb) a to control nitric oxide (NO) diffusion, but the role of this system in pulmonary circulation has not been evaluated.Wehypothesized that up-regulation ofHbainpulmonaryECs contributes to NO depletion and pulmonary vascular dysfunction in pulmonary hypertension. Primary distal pulmonary arterial vascular smooth muscle cells, lung tissue sections from unused donor (control) and idiopathic pulmonary artery (PA) hypertension lungs, and rat and mouse models of SU5416/hypoxia-induced pulmonary hypertension (PH) were used. Immunohistochemical, immunocytochemical, and immunoblot analyses and transfection, infection, DNA synthesis, apoptosis, migration, cell count, and protein activity assays were performed in this study. Cocultures of human pulmonarymicrovascular ECs and distal pulmonary arterial vascular smooth muscle cells, lung tissue from control and pulmonary hypertensive lungs, and a mouse modelof chronic hypoxia-inducedPHwere used. Immunohistochemical, immunoblot analyses, spectrophotometry, and blood vessel myography experiments were performed in this study. We find increased expression of Hb a in pulmonary endothelium from humans and mice with PH compared with controls. In addition, we show up-regulation of Hb a in human pulmonary ECs cocultured with PA smooth muscle cells in hypoxia.We treated pulmonary ECs with a Hb a mimetic peptide that disrupts the association ofHba with endothelialNOsynthase, and found that cells treated with the peptide exhibited increased NO signaling compared with a scrambled peptide. Myography experiments using pulmonary arteries from hypoxic mice show that the Hb a mimetic peptide enhanced vasodilation in response to acetylcholine.Our findings reveal that endothelial Hb a functions as an endogenous scavenger of NO in the pulmonary endothelium. Targeting this pathway may offer a novel therapeutic target to increase endogenous levels of NO in PH.

Original languageEnglish (US)
Pages (from-to)733-744
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume57
Issue number6
DOIs
StatePublished - Dec 2017

Keywords

  • Endothelial dysfunction
  • Endothelial nitric oxide synthase
  • Hemoglobin
  • Nitric oxide
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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