Polyamines in Pulmonary Vascular Biology

DOI: 10.1007/978-1-59745-145-1_11


Polyamines are essential for cell growth and development. They regulate many functions, including cell division, migration,
ion channel regulation, apoptosis, and the cellular synthesis of DNA, RNA, and proteins. A recent review on the roles of polyamines
in the lung emphasized studies on respiratory cell biology and polyamine uptake (1). The primary goal of this chapter is to review evidence that polyamines contribute to phenotypical changes in pulmonary vascular
cells that underlie the pathogenesis of pulmonary arterial hypertension. Because arginases can regulate polyamines, their
potential role in the pathogenesis of pulmonary hypertension and asthma also will be reviewed. The data suggest polyamines
may be future therapeutic targets for pulmonary hypertension, although clinical trials measuring polyamines and their regulation
are lacking.

2 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ornithine decarboxylase is the initial and rate-limiting enzyme in the polyamine biosynthetic pathway. Polyamines are found in all mammalian cells and are required for cell growth. We previously demonstrated that N-hydroxyarginine and nitric oxide inhibit tumor cell proliferation by inhibiting arginase and ornithine decarboxylase, respectively, and, therefore, polyamine synthesis. In addition, we showed that nitric oxide inhibits purified ornithine decarboxylase by S-nitrosylation. Herein we provide evidence for the chemical mechanism by which nitric oxide and S-nitrosothiols react with cysteine residues in ornithine decarboxylase to form an S-nitrosothiol(s) on the protein. The diazeniumdiolate nitric oxide donor agent 1-diethyl-2-hydroxy-2-nitroso-hydrazine acts through an oxygen-dependent mechanism leading to formation of the nitrosating agents N(2)O(3) and/or N(2)O(4). S-Nitrosoglutathione inhibits ornithine decarboxylase by an oxygen-independent mechanism likely by S-transnitrosation. In addition, we provide evidence for the S-nitrosylation of 4 cysteine residues per ornithine decarboxylase monomer including cysteine 360, which is critical for enzyme activity. Finally S-nitrosylated ornithine decarboxylase was isolated from intact cells treated with nitric oxide, suggesting that nitric oxide may regulate ornithine decarboxylase activity by S-nitrosylation in vivo.
    Journal of Biological Chemistry 10/2001; 276(37):34458-64. DOI:10.1074/jbc.M105219200 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies suggest that a nitric oxide (NO) deficiency and elevated arginase activity may play a role in the pathogenesis of asthma. Although much attention has been directed toward measurements of exhaled NO in asthma, no studies to date have evaluated levels of plasma arginase or arginine, the substrate for NO production, in patients with asthma. This study, therefore, measured amino acid levels, arginase activity, and nitric oxide metabolites in the blood of patients with asthma, as well as NO in exhaled breath. Although levels of virtually all amino acids were reduced, patients with asthma exhibited a striking reduction in plasma arginine levels compared with normal control subjects without asthma (45 +/- 22 vs. 94 +/- 29 microM, p < 0.0001), and serum arginase activity was elevated (1.6 +/- 0.8 vs. 0.5 +/- 0.3 micromol/ml/hour, asthma vs. control, p < 0.0001). High arginase activity in patients with asthma may contribute to low circulating arginine levels, thereby limiting arginine bioavailability and creating a NO deficiency that induces hyperreactive airways. Addressing the alterations in arginine metabolism may result in new strategies for treatment of asthma.
    American Journal of Respiratory and Critical Care Medicine 07/2004; 170(2):148-53. DOI:10.1164/rccm.200309-1304OC · 13.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Previous work in our laboratory has shown that the continuous administration of alpha-difluoromethylornithine (DFMO), a highly specific irreversible inhibitor of ornithine decarboxylase (ODC), which is the rate-limiting enzyme in polyamine biosynthesis, prevented the development of pulmonary hypertension and right ventricular hypertrophy induced in rats 21 days after a single injection of monocrotaline (MCT). We now report that DFMO treatment did not influence the proposed first step of MCT pneumotoxicity, that is, the hepatic metabolism of MCT to toxic pyrrolic metabolites. In contrast, DFMO treatment blunted the development of lung perivascular edema at Day 7, inhibited the respective four- and twofold increases in lung putrescine and spermidine contents at Day 21 without significantly altering spermine content, and prevented the arterial medial thickening at Day 21. It thus appears that increased lung polyamine biosynthesis may be essential for the expression of MCT-induced perivascular edema as well as the development of the medial thickening stage of MCT-induced hypertensive pulmonary vascular disease.
    Toxicology and Applied Pharmacology 11/1985; 81(1):91-9. DOI:10.1016/0041-008X(85)90124-3 · 3.71 Impact Factor
Show more