title: Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension.
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 hypoxia-inducible 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.
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas.|2 Methodist DeBakey Heart and Vascular Center, and Methodist J. C. Walter Jr. Transplant Center, the Methodist Hospital, Houston, Texas.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Garcia-Morales
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Ning-Yuan
authors.initials: NY
authors.lastname: Chen
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Tingting
authors.initials: T
authors.lastname: Weng
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Fayong
authors.initials: F
authors.lastname: Luo
authors.affiliation: 3 Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Davies
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Kemly
authors.initials: K
authors.lastname: Philip
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Volcik
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Ernestina
authors.initials: E
authors.lastname: Melicoff
authors.affiliation: 2 Methodist DeBakey Heart and Vascular Center, and Methodist J. C. Walter Jr. Transplant Center, the Methodist Hospital, Houston, Texas.
authors.forename: Javier
authors.initials: J
authors.lastname: Amione-Guerra
authors.affiliation: 2 Methodist DeBakey Heart and Vascular Center, and Methodist J. C. Walter Jr. Transplant Center, the Methodist Hospital, Houston, Texas.
authors.forename: Raquel R
authors.initials: RR
authors.lastname: Bunge
authors.affiliation: 2 Methodist DeBakey Heart and Vascular Center, and Methodist J. C. Walter Jr. Transplant Center, the Methodist Hospital, Houston, Texas.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Bruckner
authors.affiliation: 2 Methodist DeBakey Heart and Vascular Center, and Methodist J. C. Walter Jr. Transplant Center, the Methodist Hospital, Houston, Texas.
authors.forename: Matthias
authors.initials: M
authors.lastname: Loebe
authors.affiliation: 4 Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado; and.
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.affiliation: 5 Department of Internal Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Lavannya M
authors.initials: LM
authors.lastname: Pandit
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Harry
authors.initials: H
authors.lastname: Karmouty-Quintana
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000368:Aged; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D011658:Pulmonary Fibrosis / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000241:Adenosine
keywords: adenosine A2B receptor; group III pulmonary hypertension; hypoxia-inducible factor-1A; idiopathic pulmonary fibrosis; succinate