POLYAMINE REGULATORY PROCESSES AND OXIDATIVE STRESS IN MONOCROTALINE-TREATED PULMONARY-ARTERY ENDOTHELIAL-CELLS

Alterations in polyamine metabolism may be a critical mechanism of mon ocrotaline (MCT)-induced structural remodeling of the pulmonary vascul ature. In the present study, the hypothesis that MCT, through the indu ction of oxidative stress, modulates cellular polyamine regulatory mec hanisms which in turn might be involved in the upregulation of fibrone ctin production in pulmonary artery endothelial cells (PAEC) was exami ned. A 24-h treatment with MCT significantly increased PAEC polyamine concentrations as compared to vehicle-treated cells. In addition, expo sure to MCT caused an increase in abundance of ornithine decarboxylase (ODC) mRNA, upregulation of ODC activity and enhancement of spermidin e import into PAEC. Inhibition of de novo polyamine synthesis further increased spermidine uptake in MCT-treated cells. The depletion of cel lular polyamine contents through the blockade of both de novo polyamin e biosynthesis and polyamine transport prevented MCT-induced increases in the medium level of fibronectin. In addition, PAEC treatment with MCT stimulated cellular oxidative stress as determined by increased le vels of thiobarbituric acid reactive substances, enhanced dichlorofluo rescein fluorescence and activation of NF-kappa B. A co-treatment with dimethylthiourea, an oxygen radical scavenger, prevented MCT-induced increases in cellular oxidation and attenuated disturbances in polyami ne metabolism. These data suggest that MCT can stimulate polyamine reg ulatory processes in PAEC possibly through an increase in cellular oxi dative stress. The present study may have significant implication in u nderstanding mechanisms of MCT-induced pulmonary hypertension and remo deling of pulmonary vasculature. (C) 1997 Academic Press.