Arginine metabolic endotypes in pulmonary arterial hypertension
| Autor: | Suzy A.A. Comhair, Farook Jahoor, Christina C. Kao, Serpil C. Erzurum, Samuel H. Wedes, Jean W. Hsu, Kurt M. Bohren |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Pulmonary and Respiratory Medicine
medicine.medical_specialty Arginine business.industry Ornithine Pharmacology Nitric oxide Arginase Pathogenesis chemistry.chemical_compound medicine.anatomical_structure Endocrinology chemistry Internal medicine Vascular resistance Citrulline Medicine business Asymmetric dimethylarginine Original Research |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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