title: Purinergic dysregulation in pulmonary hypertension.
abstract: Despite the fact that nucleotides and adenosine help regulate vascular tone through purinergic signaling pathways, little is known regarding their contributions to the pathobiology of pulmonary arterial hypertension, a condition characterized by elevated pulmonary vascular resistance and remodeling. Even less is known about the potential role that alterations in CD39 (ENTPD1), the ectonucleotidase responsible for the conversion of the nucleotides ATP and ADP to AMP, may play in pulmonary arterial hypertension. In this study we identified decreased CD39 expression on the pulmonary endothelium of patients with idiopathic pulmonary arterial hypertension. We next determined the effects of CD39 gene deletion in mice exposed to normoxia or normobaric hypoxia (10% oxygen). Compared with controls, hypoxic CD39(-/-) mice were found to have a markedly elevated ATP-to-adenosine ratio, higher pulmonary arterial pressures, more right ventricular hypertrophy, more arterial medial hypertrophy, and a pro-thrombotic phenotype. In addition, hypoxic CD39(-/-) mice exhibited a marked increase in lung P2X1 receptors. Systemic reconstitution of ATPase and ADPase enzymatic activities through continuous administration of apyrase decreased pulmonary arterial pressures in hypoxic CD39(-/-) mice to levels found in hypoxic CD39(+/+) controls. Treatment with NF279, a potent and selective P2X1 receptor antagonist, lowered pulmonary arterial pressures even further. Our study is the first to implicate decreased CD39 and resultant alterations in circulating purinergic signaling ligands and cognate receptors in the pathobiology of pulmonary arterial hypertension. Reconstitution and receptor blocking experiments suggest that phosphohydrolysis of purinergic nucleotide tri- and diphosphates, or blocking of the P2X1 receptor could serve as treatment for pulmonary arterial hypertension.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; shv@med.umich.edu.
authors.forename: Scott H
authors.identifier: 0000-0002-4595-1657
authors.initials: SH
authors.lastname: Visovatti
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Hyman
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Cardiovascular Medicine, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan; and.
authors.forename: Sascha N
authors.initials: SN
authors.lastname: Goonewardena
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan;
authors.forename: Anuli C
authors.initials: AC
authors.lastname: Anyanwu
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Cardiovascular Medicine, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan; and.
authors.forename: Yogendra
authors.initials: Y
authors.lastname: Kanthi
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Patrick
authors.initials: P
authors.lastname: Robichaud
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Jintao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Danica
authors.initials: D
authors.lastname: Petrovic-Djergovic
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Rahul
authors.initials: R
authors.lastname: Rattan
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Burant
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan;
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000959:Antihypertensive Agents / Q000494:pharmacology; D001081:Apyrase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D062186:Arterial Pressure; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D006868:Hydrolysis; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058474:Receptors, Purinergic P2X1 / Q000187:drug effects / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction; D013498:Suramin / Q000031:analogs & derivatives / Q000494:pharmacology; D066253:Vascular Remodeling; D020257:Ventricular Remodeling
chemical_list: D015703:Antigens, CD; D000959:Antihypertensive Agents; C114657:NF 279; D058920:Purinergic P2X Receptor Antagonists; D058474:Receptors, Purinergic P2X1; D013498:Suramin; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine
keywords: CD39; P2X1; ectonucleotidase; pulmonary hypertension; purinergic signaling