title: Putrescine transport in hypoxic rat main PASMCs is required for p38 MAP kinase activation.
abstract: Hypoxic pulmonary vascular remodeling in rats is associated with increased polyamine transport in pulmonary artery smooth muscle cells (PASMCs). We therefore defined constitutive and hypoxia-induced polyamine transport properties of rat cultured PASMCs and determined the impact of polyamine transport blockade on hypoxia-induced accumulation of p38 MAP kinase. PASMCs exhibited polyamine transport pathways that were characterized by Michaelis-Menten kinetics. RNA synthesis inhibition attenuated while inhibition of protein synthesis increased polyamine uptake, thus suggesting regulation by ornithine decarboxylase-antizyme. The presence of two transporters with overlapping selectivities, one for putrescine and another for all three polyamines, was inferred by cross-competition studies and by findings that only putrescine uptake was sodium dependent and that hypoxia caused a selective, time-dependent induction of putrescine transport. The pathophysiological significance of augmented putrescine import was suggested by the observation that polyamine transport inhibition suppressed hypoxia-induced p38 MAP kinase phosphorylation. These results indicate that rat PASMCs express two polyamine transporters and that a specific increase in the putrescine uptake pathway is necessary for hypoxia-induced activation of p38 MAP kinase.
authors.affiliation: Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
authors.forename: Mykhaylo
authors.initials: M
authors.lastname: Ruchko
authors.forename: Mark N
authors.initials: MN
authors.lastname: Gillespie
authors.forename: Reitha S
authors.initials: RS
authors.lastname: Weeks
authors.forename: Jack W
authors.initials: JW
authors.lastname: Olson
authors.forename: Pavel
authors.initials: P
authors.lastname: Babal
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011073:Polyamines / Q000493:pharmacokinetics; D011651:Pulmonary Artery / Q000378:metabolism*; D011700:Putrescine / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000502:physiology; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C417042:ORI 1202; D011073:Polyamines; D003609:Dactinomycin; D013096:Spermine; D003513:Cycloheximide; D012964:Sodium; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008239:Lysine; D011700:Putrescine