Regulation of ornithine decarboxylase by hypoxia in pulmonary
artery smooth muscle cells.
Harrod, Kevin S., Jack W. Olson, and Mark N. Gillespie.
Division of Pharmacology and Experimental Therapeutics, College of
Pharmacy, University of Kentucky, A.B. Chandler Medical Center,
Lexington, Kentucky
APStracts 3:0026L, 1996.
The polyamines are a family of low molecular weight organic cations
that play essential intracellular regulatory roles in cell growth and
differentiation. Elevations in cellular polyamine contents necessary
for most physiologic and pathologic events in the lung appear to be
driven by increased de novo synthesis. In contrast, increases in lung
cell polyamines required for hypoxic pulmonary vascular disease can
be attributed to augmented transmembrane polyamine transport which
may, in turn, be the result of hypoxia-related decreases in the
activity of the initial and generally rate-limiting enzyme in de novo
polyamine synthesis, ornithine decarboxylase (ODC). To begin to
define the unusual mechanism whereby hypoxia governs polyamine
regulatory pathways, the present study examined the impact of varying
severity and durations of hypoxic exposure on ODC activity and mRNA
content in cultured bovine main pulmonary artery smooth muscle cells.
The effect of hypoxia on the activity of another rate-limiting enzyme
in polyamine synthesis, S-adenosylmethionine decarboxylase (AdoMet
-DC), also was examined. Hypoxia caused time-dependent decreases in
ODC and AdoMet-DC activities that were related to the severity of
hypoxic exposure. Likewise, ODC mRNA content also was depressed by
hypoxic exposure. The relationship between the decline in ODC
activity and mRNA content was roughly linear. To determine whether
hypoxia impairs ODC mRNA stability, two different inhibitors of
transcription and Northern analyses were used to follow the decay in
ODC mRNA abundance in hypoxic and normoxic PASMCs. Densitometric
scanning of Northern analysis indicated that ODC mRNA stability did
not differ between hypoxic and normoxic PASMCs. These results suggest
that the reduction in ODC activity provoked by hypoxia in cultured
bovine PASMCs can be ascribed in part to a diminished transcriptional
rate rather than to alterations in mRNA stability.
Received 27 September 1995; accepted in final form 25 January
1996.
APS Manuscript Number L286-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 8 February 96