Stimulation of tissue-type plasminogen activator expression by retinoic acid in human endothelial cells requires retinoic acid receptor β2 induction
article
We previously showed the involvement of retinoic acid receptor α (RARα) in the induction of tissue-type plasminogen activator (t-PA) synthesis by RA in human umbilical vein endothelial cells (HUVECs). However, the rather slow onset of this induction of t-PA synthesis suggested an indirect role of RARα. Here, we show that the protein synthesis inhibitor, cycloheximide completely blocks the induction of t-PA by RA, which points to the need of an intermediary protein in t-PA stimulation. This intermediary protein is likely to be RARβ2 on the basis of the following findings: (1) the induction of RARβ by RA exactly precedes that of t-PA; (2) HUVECs with elevated RARβ mRNA levels show an undelayed t-PA induction on stimulation with RA, and this response can be almost completely inhibited with an RAR antagonist; and (3) an antisense oligodeoxynucleotide against the translation initiation site of RARβ2 mRNA greatly reduces the t-PA induction by RA. Thus, induction of t-PA by RA in HUVECs involves a 2-step mechanism requiring induction of RARβ2 via RARα, followed by induction of t-PA synthesis via RARβ2. Each of these steps is shown to have a different activation profile with RA and 9-cis RA. Chemicals/CAS: Benzoates; Chromans; Cycloheximide, 66-81-9; DNA, Complementary; Oligonucleotides, Antisense; Protein Synthesis Inhibitors; Receptors, Retinoic Acid; retinoic acid receptor alpha; retinoic acid receptor beta; Ro 41-5253, 144092-31-9; Tissue Plasminogen Activator, EC 3.4.21.68; Tretinoin, 302-79-4
Topics
Antisense oligodeoxynucleotideCycloheximideTetinoic acid receptorAlternative rna splicingAntibody responseCell stimulationcompetitive inhibitionEndothelium cellEnzyme active siteFibrinolysisGene inductionHuman cellProtein degradationBase SequenceBenzoatesCells, CulturedChromansCycloheximideDNA, ComplementaryEndothelium, VascularGene Expression RegulationHumansMolecular Sequence DataOligonucleotides, AntisenseProtein Synthesis InhibitorsReceptors, Retinoic AcidTissue Plasminogen ActivatorTretinoinUmbilical Veins
TNO Identifier
233401
ISSN
00064971
Source
Blood, 88(2), pp. 531-541.
Pages
531-541
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