Regulation of ornithine decarboxylase and polyamine import by hypoxia in pulmonary artery endothelial cells

Abstract

In rat lung and cultured lung vascular cells, hypoxia decreases ornithine decarboxylase (ODC) activity and increases polyamine import. In this study, we used rat cultured pulmonary artery endothelial cells to explore the mechanism of hypoxia-induced reduction in ODC activity and determined whether this event was functionally related to the increase in polyamine import. Two strategies known to suppress proteasome-mediated ODC degradation, lactacystin treatment and use of cells expressing a truncated ODC incapable of interacting with the proteasome, prevented the hypoxia-induced decrease in ODC activity. Interestingly, though, cellular abundance of the 24-kDa antizyme, a known physiological accelerator of ODC degradation, was not increased by hypoxia. These observations suggest that an antizyme-independent ODC degradation pathway contributes to hypoxia-induced reductions of ODC activity. When reductions in ODC activity in hypoxia were prevented by the proteasome inhibitor strategies, hypoxia failed to increase polyamine transport. The induction of polyamine transport in hypoxic pulmonary artery endothelial cells thus seems to require decreased ODC activity as an initiating event.

The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

“…Initial studies on apoptosis in thymocytes observed polyamine depletion as an unsuspected finding and hypothesized that polyamine depletion contributed to the activation of apoptosis (25). Agmatine depletes intracellular polyamine levels to suppress growth (4,16,22,29,46,59,68). Supplementation with the polyamine putrescine attenuates this effect (22,33,59).…”

“…Ras/3T3 cells were collected and lysed [lysis buffer contained 1% Triton X-100, 0.5% deoxycholic acid, 1 mM EDTA, 0.1% SDS, 4 mM NaF, complete protease cocktail (Roche Molecular Biochemicals, Mannheim, Germany), 0.7 g/ml pepstatin, and 1 mM NaVO 4 in PBS]. Lysates at 50 g/lane were resolved on 12% NuPAGE gels in MOPS buffer (Invitrogen, Carlsbad, CA).…”

“…Agmatine suppresses growth through the reduction of intracellular polyamine levels, which are required for growth, and inhibition of ornithine decarboxylase (ODC), the first and rate-limiting enzyme of polyamine biosynthesis, in all models studied to date (4,16,22,29,46,59,68). Reduction of cellular polyamine levels occurs by the induction of the polyamine autoregulatory protein antizyme (4,29,59), increasing activity of polyamine catabolism (16,68), and/or decreasing ODC activity by another mechanism, possibly by reduction of ODC translation (4,71). Furthermore, agmatine is transported into mammalian cells via the polyamine transport system (57).…”

Induction of Hypersensitive Cell Death by Hydrogen Peroxide Produced through Polyamine Degradation in Tobacco Plants

“…One possibility is that plants are equipped with two alternative pathways for polyamine biosynthesis that function independently in the plant defense network. Another possibility is that Arg decarboxylase regulates polyamine levels in a similar manner as in mammalian cells, in which agmatine, a product of Arg decarboxylase, has been shown to exert effects by inducing an antizyme for ODC (Babal et al, 2001). …”

Agmatine Is Efficiently Transported by Non-Neuronal Monoamine Transporters Extraneuronal Monoamine Transporter (EMT) and Organic Cation Transporter 2 (OCT2)

“…Arginine decarboxylase activity is associated with mitochondrial membranes and is most prevalent in kidney, liver, and brain (Lortie et al, 1996). Agmatine is present in plasma and is widely but unevenly distributed in mammalian tissue (Raasch et al, 1995).There is evidence that agmatine acts as an antiproliferative molecule through induction of the protein antizyme (Satriano et al, 1998;Babal et al, 2001). Antizyme inhibits ornithine decarboxylase and hence polyamine (putrescine, spermine, and spermidine) biosynthesis.…”