title: An arginase-1 SNP that protects against the development of pulmonary hypertension in bronchopulmonary dysplasia enhances NO-mediated apoptosis in lymphocytes.
abstract: Arginase and nitric oxide synthase (NOS) share a common substrate, l-arginine, and have opposing effects on vascular remodeling. Arginase is the first step in polyamine and proline synthesis necessary for cellular proliferation, while NO produced from NOS promotes apoptosis. Previously, we identified a single nucleotide polymorphism (SNP) in the arginase-1 (ARG1) gene, rs2781666 (T-allele) that was associated with a decreased risk for developing pulmonary hypertension (PH) in a cohort of infants with bronchopulmonary dysplasia (BPD). In this study, we utilized lymphocytes from neonates (the only readily available cells from these patients expressing the two genotypes of interest) with either the rs2781666 SNP (TT) or wild type (GG) to test the hypothesis that the protection of the ARG1 SNP against the development of PH in BPD would involve augmented NO production leading to more apoptosis. Lymphocytes were stimulated with IL-4, IL-13, and phorbol myristate acetate (PMA). We found that TT lymphocytes had similar levels of arginase I and arginase II expression, but there was a tendency for lower urea production (a surrogate marker of arginase activity), than in the GG lymphocytes. The TT lymphocytes also had significantly greater NO production than did GG lymphocytes despite no differences in iNOS expression between genotypes. Furthermore, the TT lymphocytes had lower numbers of viable cells, and higher levels of cleaved caspase-3 than did GG lymphocytes. Inhibiting NOS activity using Nω-Nitro-l-arginine methyl ester hydrochloride (l-NAME) significantly decreased cleaved caspase-3 levels in the TT lymphocytes. These data demonstrate that the TT genotype results in greater levels of NO production leading to more apoptosis, which is consistent with the concept that BPD patients with the TT genotype are protected against the development of PH by producing greater basal levels of endogenous NO.
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, The Ohio State University, Columbus, Ohio Jennifer.Trittmann@NationwideChildrens.org.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Trittmann
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, The Ohio State University, Columbus, Ohio.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, The Ohio State University, Columbus, Ohio.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.|Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio.
authors.forename: Louis G
authors.initials: LG
authors.lastname: Chicoine
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, The Ohio State University, Columbus, Ohio.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, The Ohio State University, Columbus, Ohio.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chen
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, The Ohio State University, Columbus, Ohio.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Leif D
authors.initials: LD
authors.lastname: Nelin
mesh_terms: D017209:Apoptosis; D001119:Arginase / Q000378:metabolism*; D001120:Arginine; D001997:Bronchopulmonary Dysplasia / Q000150:complications* / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D015331:Cohort Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007231:Infant, Newborn; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014508:Urea / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; D014508:Urea; D001120:Arginine; D019001:Nitric Oxide Synthase; D053148:Caspase 3; C574619:ARG1 protein, human; D001119:Arginase; D010100:Oxygen
keywords: Bronchopulmonary dysplasia; neonate; oxygen; preterm; urea cycle