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Hydralazine differentially increases messenger rnas for the alpha and beta subunits of prolyl 4 hydroxylase whereas it decreases pro alpha 1 i collagen messenger rnas in human skin fibroblasts



Hydralazine differentially increases messenger rnas for the alpha and beta subunits of prolyl 4 hydroxylase whereas it decreases pro alpha 1 i collagen messenger rnas in human skin fibroblasts



Archives of Biochemistry & Biophysics 289(2): 399-404



We have used specific oligonucleotide probes to measure the effect of hydralazine on mRNA levels of the .alpha. and .beta. subunits of prolyl 4-hydroxylase (PH), a key posttranslational modifying enzyme in collagen biosynthesis. Hydralazine exerts a paradoxical effect on collagen biosynthesis in cultured fibroblasts. Cells exposed to hydralazine synthesize substantially reduced amounts of collagen, which is severely deficient in hydroxyproline. Surprisingly, however, the level of prolyl hydroxylase activity assayed in extracts of treated cells is markedly increased, suggesting overproduction of the enzyme. Hybridization analysis indicated that in utreated cells the concentration of the .alpha.PH subunit mRNA was about 20-25% of the .beta.PH subunit mRNA concentration. Hydralazine treatment increased the mRNAs for both .alpha. and .beta. subunits of the PH by three- to fourfold. A differential induction of these mRNAs was observed, however. The .alpha. subunit mRNA was maximally increased within 24 h, whereas the .beta. subunit mRNA was increased more slowly, reaching a maximum at 72 h. In contrast, the 5.8 and 4.8-kb mRNAs for pro.alpha.1(I) collagen were virtually eliminated by 72 h. This study demonstrates that the increased prolyl hydroxylase activity is a direct result of hydralazine-mediated increases in steady state mRNA content for the .alpha. and .beta. subunits of this enzyme. Moreover, the earlier induction of .alpha.PH mRNA may provide the first evidence at the mRNA level that regulation of PH activity occurs mainly through the regulation of the .alpha. subunit of PH. In addition, the decrease in collagen synthesis by hydralazine appears to result directly from suppression of both species of mRNA for pro.alpha.1(I) collagen.

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Accession: 007412310

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