Altered hypoxic-adenosine axis and metabolism in group III pulmonary hypertension

Luis J. Garcia-Morales, Ning Yuan Chen, Tingting Weng, Fayong Luo, Jonathan Davies, Kemly Philip, Kelly A. Volcik, Ernestina Melicoff, Javier Amione-Guerra, Raquel R. Bunge, Brian A. Bruckner, Matthias Loebe, Holger K. Eltzschig, Lavannya M. Pandit, Michael R. Blackburn, Harry Karmouty-Quintana

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Group III pulmonary hypertension (PH) is a highly prevalent and deadly lung disorder with limited treatment options other than transplantation. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). Between 30 and 40% of patients with IPF are diagnosed with PH. The diagnosis of PH has devastating consequences to these patients, leading to increased morbidity and mortality, yet the molecular mechanisms involved in the development of PH in patients with chronic lung disease remain elusive. Our hypothesis was that the hypoxic-adenosinergic system is enhanced in patients with group III PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxiainducible factor (HIF)-1A, adenosine A2B receptor, CD73, and equilibrative nucleotide transporter-1. In addition, we assessed whether altered mitochondrial metabolism was present in these samples. Increased expression of HIF-1A was observed in tissues from patients with group III PH. These changes were consistent with increased evidence of adenosine accumulation in group III PH. A novel observation of our study was of evidence suggesting altered mitochondrial metabolism in lung tissue from group III PH leading to increased succinate levels that are able to further stabilize HIF-1A. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in group III PH and that subsequent succinate accumulation may play a part in the development of group III PH.

Original languageEnglish (US)
Pages (from-to)574-583
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume54
Issue number4
DOIs
StatePublished - Apr 2016
Externally publishedYes

Keywords

  • Adenosine A2B receptor
  • Group III pulmonary hypertension
  • Hypoxiainducible factor-1A
  • Idiopathic pulmonary fibrosis
  • Succinate

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Altered hypoxic-adenosine axis and metabolism in group III pulmonary hypertension'. Together they form a unique fingerprint.

Cite this