Modulation of plasminogen activator inhibitor type-1 biosynthesis in vitro and in vivo with oligo(nucleoside phosphorothioate)s and related constructs
Identifieur interne : 001434 ( Istex/Checkpoint ); précédent : 001433; suivant : 001435Modulation of plasminogen activator inhibitor type-1 biosynthesis in vitro and in vivo with oligo(nucleoside phosphorothioate)s and related constructs
Auteurs : Włodzimierz Buczko [Pologne] ; Czesław Cierniewski [Pologne] ; Anna Kobyla Ska [Pologne] ; Maria Koziołkiewicz [Pologne] ; And Rzej Okruszek [Pologne] ; Zofia Pawłowska [Pologne] ; Elzbzieta Pluskota [Pologne] ; Wojciech J. Stec [Pologne]Source :
- Pharmacology and Therapeutics [ 0163-7258 ] ; 1997.
English descriptors
- Teeft :
- Activator, Agrawal, Analogue, Antisense, Antisense oligonucleotide, Antisense oligonucleotides, Antisense phospho, Antisense phosphorothioate, Antisense research, Biol, Biosynthesis, Buczko, Cellular uptake, Chem, Control oligonucleotides, Endothelial, Endothelial cells, Experimental thrombosis, Heptadecanol, Human aortic, Human plasma, Human umbilical vein, Huvec, Incubation time, Inhibition, Inhibitor, Inhibitory, Koziolkiewicz, Loskutoff, Menthol, Mismatch, Mrna, Muscle cells, Myocardial infarction, Nucl, Nucleotide, Oligodeoxyribonucleotide, Oligodeoxyribonucleotides, Oligonucleotide, Oligonucleotide concentration, Oligonucleotides, Peptide, Phos, Phospho, Phosphodiester, Phosphorothioate, Phosphorothioate oligonucleotides, Phosphorothioates, Plasminogen, Plasminogen activator, Plasminogen activator inhibitor, Plasminogen activator inhibitor type, Plasminogen activators, Rnase, Rothioate, Smooth muscle cells, Stec, Stereocontrolled synthesis, Thromb, Thrombosis, Thrombus, Thrombus formation, Umbilical, Wilk.
Abstract
Abstract: Oligonucleotides with a nucleotide sequence complementary to various regions of human plasminogen activator inhibitor type-1 (PAI-1) mRNA have been studied as antisense inhibitors of expression of PAI-1 protein in cultured cells [human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells, human hybrid endothelial cells]. Hexadeca(deoxyribonucleoside phosphorothioate) 13 complementary to a fragment of a signal peptide PAI-1 mRNA was found to be most active, giving ca. 70% inhibition of PAI-1 release in a time- and dose-dependent way. The stereo-regular A11-SP and All-RP diastereomers of 13 were studied and found to inhibit PAI-1 synthesis in HUVEC in a stereo-dependent manner, with the All-SP diastereomer considerably more active than the stereo-random construct and All-RP isomer. The observed stereo-dependent activity of oligonucleotide phosphorothioate constructs is presumably governed by their resistance to nucleases. The corresponding phosphodiester analogue of 13 was not active unless covalently bound at its 5′-end to a lipophilic alcohol residue (menthol, heptadecanol). The observed antisense activity of phosphodiester oligonucleotide bioconjugates in cultured human hybrid endothelial cells was paralleled by their increased stability in human plasma with respect to unconjugated oligonucleotide. The oligo(deoxyribonucleoside phosphorothioate) complementary to the same signal peptide region of rat PAI-1 mRNA was found to reduce the PAI-1 level in blood plasma of rats after intravenous administration into the tail vein. The effect was both time- and dose-dependent. The same oligonucleotide was found to protect against arterial thrombus formation in the rat (lower incidence of venous thrombosis, lower thrombus weight, and increased occlusion time in experimentally induced thrombosis). An anti-PAI-1 inhibitory activity has been independently reported for a 20-mer oligo(2′-O-methyl-ribonucleoside phosphorothioate) complementary to a 3′-untranslated region of human PAI-1 mRNA in cultured HUVEC and human aortic smooth muscle cells.
Url:
DOI: 10.1016/S0163-7258(97)00091-0
Affiliations:
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Stec</name><affiliation wicri:level="1"><country xml:lang="fr">Pologne</country><wicri:regionArea>Polish Academy of Sciences, Center Of Molecular And Macromolecular Studies, department of bioorganic chemistry, Łódź</wicri:regionArea><wicri:noRegion>Łódź</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j">Pharmacology and Therapeutics</title><title level="j" type="abbrev">JPT</title><idno type="ISSN">0163-7258</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1997">1997</date><biblScope unit="volume">76</biblScope><biblScope unit="issue">1–3</biblScope><biblScope unit="page" from="161">161</biblScope><biblScope unit="page" to="175">175</biblScope></imprint><idno type="ISSN">0163-7258</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0163-7258</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Activator</term><term>Agrawal</term><term>Analogue</term><term>Antisense</term><term>Antisense oligonucleotide</term><term>Antisense oligonucleotides</term><term>Antisense phospho</term><term>Antisense phosphorothioate</term><term>Antisense research</term><term>Biol</term><term>Biosynthesis</term><term>Buczko</term><term>Cellular uptake</term><term>Chem</term><term>Control oligonucleotides</term><term>Endothelial</term><term>Endothelial cells</term><term>Experimental thrombosis</term><term>Heptadecanol</term><term>Human aortic</term><term>Human plasma</term><term>Human umbilical vein</term><term>Huvec</term><term>Incubation time</term><term>Inhibition</term><term>Inhibitor</term><term>Inhibitory</term><term>Koziolkiewicz</term><term>Loskutoff</term><term>Menthol</term><term>Mismatch</term><term>Mrna</term><term>Muscle cells</term><term>Myocardial infarction</term><term>Nucl</term><term>Nucleotide</term><term>Oligodeoxyribonucleotide</term><term>Oligodeoxyribonucleotides</term><term>Oligonucleotide</term><term>Oligonucleotide concentration</term><term>Oligonucleotides</term><term>Peptide</term><term>Phos</term><term>Phospho</term><term>Phosphodiester</term><term>Phosphorothioate</term><term>Phosphorothioate oligonucleotides</term><term>Phosphorothioates</term><term>Plasminogen</term><term>Plasminogen activator</term><term>Plasminogen activator inhibitor</term><term>Plasminogen activator inhibitor type</term><term>Plasminogen activators</term><term>Rnase</term><term>Rothioate</term><term>Smooth muscle cells</term><term>Stec</term><term>Stereocontrolled synthesis</term><term>Thromb</term><term>Thrombosis</term><term>Thrombus</term><term>Thrombus formation</term><term>Umbilical</term><term>Wilk</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Oligonucleotides with a nucleotide sequence complementary to various regions of human plasminogen activator inhibitor type-1 (PAI-1) mRNA have been studied as antisense inhibitors of expression of PAI-1 protein in cultured cells [human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells, human hybrid endothelial cells]. Hexadeca(deoxyribonucleoside phosphorothioate) 13 complementary to a fragment of a signal peptide PAI-1 mRNA was found to be most active, giving ca. 70% inhibition of PAI-1 release in a time- and dose-dependent way. The stereo-regular A11-SP and All-RP diastereomers of 13 were studied and found to inhibit PAI-1 synthesis in HUVEC in a stereo-dependent manner, with the All-SP diastereomer considerably more active than the stereo-random construct and All-RP isomer. The observed stereo-dependent activity of oligonucleotide phosphorothioate constructs is presumably governed by their resistance to nucleases. The corresponding phosphodiester analogue of 13 was not active unless covalently bound at its 5′-end to a lipophilic alcohol residue (menthol, heptadecanol). The observed antisense activity of phosphodiester oligonucleotide bioconjugates in cultured human hybrid endothelial cells was paralleled by their increased stability in human plasma with respect to unconjugated oligonucleotide. The oligo(deoxyribonucleoside phosphorothioate) complementary to the same signal peptide region of rat PAI-1 mRNA was found to reduce the PAI-1 level in blood plasma of rats after intravenous administration into the tail vein. The effect was both time- and dose-dependent. The same oligonucleotide was found to protect against arterial thrombus formation in the rat (lower incidence of venous thrombosis, lower thrombus weight, and increased occlusion time in experimentally induced thrombosis). An anti-PAI-1 inhibitory activity has been independently reported for a 20-mer oligo(2′-O-methyl-ribonucleoside phosphorothioate) complementary to a 3′-untranslated region of human PAI-1 mRNA in cultured HUVEC and human aortic smooth muscle cells.</div></front></TEI><affiliations><list><country><li>Pologne</li></country></list><tree><country name="Pologne"><noRegion><name sortKey="Buczko, Wlodzimierz" sort="Buczko, Wlodzimierz" uniqKey="Buczko W" first="Włodzimierz" last="Buczko">Włodzimierz Buczko</name></noRegion><name sortKey="Cierniewski, Czeslaw" sort="Cierniewski, Czeslaw" uniqKey="Cierniewski C" first="Czesław" last="Cierniewski">Czesław Cierniewski</name><name sortKey="Kobyla Ska, Anna" sort="Kobyla Ska, Anna" uniqKey="Kobyla Ska A" first="Anna" last="Kobyla Ska">Anna Kobyla Ska</name><name sortKey="Koziolkiewicz, Maria" sort="Koziolkiewicz, Maria" uniqKey="Koziolkiewicz M" first="Maria" last="Koziołkiewicz">Maria Koziołkiewicz</name><name sortKey="Okruszek, And Rzej" sort="Okruszek, And Rzej" uniqKey="Okruszek A" first="And Rzej" last="Okruszek">And Rzej Okruszek</name><name sortKey="Pawlowska, Zofia" sort="Pawlowska, Zofia" uniqKey="Pawlowska Z" first="Zofia" last="Pawłowska">Zofia Pawłowska</name><name sortKey="Pluskota, Elzbzieta" sort="Pluskota, Elzbzieta" uniqKey="Pluskota E" first="Elzbzieta" last="Pluskota">Elzbzieta Pluskota</name><name sortKey="Stec, Wojciech J" sort="Stec, Wojciech J" uniqKey="Stec W" first="Wojciech J." last="Stec">Wojciech J. 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