TY - JOUR
T1 - Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension
AU - Garcia-Morales, Luis J
AU - Chen, Ning-Yuan
AU - Weng, Tingting
AU - Luo, Fayong
AU - Davies, Jonathan
AU - Philip, Kemly
AU - Volcik, Kelly A
AU - Melicoff, Ernestina
AU - Amione-Guerra, Javier
AU - Bunge, Raquel R
AU - Bruckner, Brian A
AU - Loebe, Matthias
AU - Eltzschig, Holger K
AU - Pandit, Lavannya M
AU - Blackburn, Michael R
AU - Karmouty-Quintana, Harry
PY - 2015/9/28
Y1 - 2015/9/28
N2 - BACKGROUND: 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 30-40% 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 is that the hypoxic-adenosinergic system is enhanced in patients with Group III PH compared to IPF patients with no PH.METHODS AND RESULTS: Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis including expression levels of HIF-1A, ADORA2B, CD73 and ENT-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 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.CONCLUSIONS: 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.
AB - BACKGROUND: 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 30-40% 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 is that the hypoxic-adenosinergic system is enhanced in patients with Group III PH compared to IPF patients with no PH.METHODS AND RESULTS: Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis including expression levels of HIF-1A, ADORA2B, CD73 and ENT-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 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.CONCLUSIONS: 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.
UR - https://www.scopus.com/pages/publications/84963780889
UR - https://www.scopus.com/inward/citedby.url?scp=84963780889&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2015-0145OC
DO - 10.1165/rcmb.2015-0145OC
M3 - Article
C2 - 26414702
SN - 1044-1549
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
ER -