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YC-1 Stimulates the Expression of Gaseous Monoxide-Generating Enzymes in Vascular Smooth Muscle Cells

dc.contributor.authorLiu, Xiao-Mingen_US
dc.contributor.authorPeyton, Kelly J.en_US
dc.contributor.authorMendelev, Natalia N.en_US
dc.contributor.authorWang, Hongen_US
dc.contributor.authorTulis, David A.en_US
dc.contributor.authorDurante, Williamen_US
dc.date.accessioned2011-04-15T15:46:50Zen_US
dc.date.accessioned2011-05-17T00:56:28Z
dc.date.available2011-04-15T15:46:50Zen_US
dc.date.available2011-05-17T00:56:28Z
dc.date.issued2009-01en_US
dc.description.abstractThe benzylindazole derivative 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1) is an allosteric stimulator of soluble guanylate cyclase (sGC) that sensitizes the enzyme to the gaseous ligands carbon monoxide (CO) and nitric oxide (NO). In this study, we examined whether YC-1 also promotes the production of these gaseous monoxides by stimulating the expression of the inducible isoforms of heme oxygenase (HO-1) and NO synthase (iNOS) in vascular smooth muscle cells (SMCs). YC-1 increased HO-1 mRNA, protein, and promoter activity and potentiated cytokine-mediated expression of iNOS protein and NO synthesis by SMCs. The induction of HO-1 by YC-1 was unchanged by the sGC inhibitor, 1H-(1,2,4)oxadiazolo[4,3-α]quinozalin-1-one (ODQ) or by the protein kinase G inhibitors (8R,9S,11S)-(-)-2-methyl-9-methoxyl-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cyclocta9(cde)trinen-1-one (KT 5823) and YGRKKRRQRRRPPLRKKKKKH-amide (DT-2) and was not duplicated by 8-bromo-cGMP or the NO-independent sGC stimulator 5-cyclopropyl-2[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-yl] pyrimidin-4-ylamine (BAY 41-2272). However, the YC-1-mediated induction of HO-1 was inhibited by the phosphatidylinositol-3-kinase (PI3K) inhibitors wortmannin and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002). In contrast, the enhancement of cytokine-stimulated iNOS expression and NO production by YC-1 was prevented by ODQ and the protein kinase A inhibitor (9S,10S, 12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9, 12-epoxy-1H-diindolo(1,2,3-fg:3′,2′,1′-kl)pyrrolo(3,4-i)(1,6)-benzodiazocine-10-carboxylic acid hexyl ester (KT 5720) and was mimicked by 8-bromo-cGMP and BAY 41-2272. In conclusion, these studies demonstrate that YC-1 stimulates the expression of HO-1 and iNOS in vascular SMCs via the PI3K and sGC-cGMP-protein kinase A pathway, respectively. The ability of YC-1 to sensitize sGC to gaseous monoxides and simultaneously stimulate their production through the induction of HO-1 and iNOS provides a potent mechanism by which the cGMP-dependent and -independent biological actions of this agent are amplified. Originally published Molecular Pharmacology, Vol. 75, No. 1, Jan 2009en_US
dc.identifier.citationMolecular Pharmacology; 75:1 p. 208-217en_US
dc.identifier.pmidPMC2606927en_US
dc.identifier.urihttp://hdl.handle.net/10342/3332en_US
dc.language.isoen_USen_US
dc.publisherEast Carolina Universityen_US
dc.relation.urihttp://molpharm.aspetjournals.org/content/75/1/208en_US
dc.rightsAuthor notified of opt-out rights by Cammie Jennings prior to upload of this article.en_US
dc.subjectYC-1en_US
dc.subjectMonoxide-generating enzymesen_US
dc.subjectSmooth muscleen_US
dc.titleYC-1 Stimulates the Expression of Gaseous Monoxide-Generating Enzymes in Vascular Smooth Muscle Cellsen_US
dc.typeArticleen_US

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