Putrescine transport in hypoxic rat main PASMCs is required for p38 MAP kinase activation.
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.
Ruchko
Mykhaylo
M
Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
Gillespie
Mark N
MN
Weeks
Reitha S
RS
Olson
Jack W
JW
Babal
Pavel
P
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
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