title: Arginine metabolic endotypes in pulmonary arterial hypertension.
abstract: Decreased synthesis of nitric oxide (NO) by NO synthases (NOS) is believed to play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). Multiple factors may contribute to decreased NO bioavailability, including increased activity of arginase, the enzyme that converts arginine to ornithine and urea, which may compete with NOS for arginine; inadequate de novo arginine production from citrulline; and increased concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS. We hypothesized that PAH patients with the lowest arginine availability secondary to increased arginase activity and/or inadequate de novo arginine synthesis might have a slower rate of NO synthesis and greater pulmonary vascular resistance. Nine patients with group 1 PAH and 10 healthy controls were given primed, constant intravenous infusions of (15)N2-arginine, (13)C,(2)H4-citrulline, (15)N2-ornithine, and (13)C-urea in the postabsorptive state. The results showed that, compared with healthy controls, PAH patients had a tendency toward increased arginine clearance and ornithine flux but no difference in arginine and citrulline flux, de novo arginine synthesis, or NO synthesis. Arginine-to-ADMA ratio was increased in PAH patients. Two endotypes of patients with low and high arginase activity were identified; compared with the low-arginase group, the patients with high arginase had increased arginine flux, slower NO synthesis, and lower plasma concentrations of ADMA. These results demonstrate that increased breakdown of arginine by arginase occurs in PAH and affects NO synthesis. Furthermore, there is no compensatory increase in de novo arginine synthesis to overcome this increased utilization of arginine by arginase.
authors.affiliation: Section of Pulmonary, Critical Care, and Sleep, Baylor College of Medicine, Houston, Texas, USA ; Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Christina C
authors.initials: CC
authors.lastname: Kao
authors.affiliation: Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Wedes
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jean W
authors.initials: JW
authors.lastname: Hsu
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Bohren
authors.affiliation: Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Suzy A A
authors.initials: SA
authors.lastname: Comhair
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Farook
authors.initials: F
authors.lastname: Jahoor
authors.affiliation: Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
keywords: arginase; asymmetric dimethylarginine; nitric oxide; ornithine