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

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)
William Durante (Creator)
Xiao-ming Liu (Creator)
Natalia N. Mendelev (Creator)
Kelly J. Peyton (Creator)
David A. Tulis (Creator)
Hong Wang (Creator)
East Carolina University (ECU )
Web Site: http://www.ecu.edu/lib/

Abstract: The 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 2009

Additional Information

Molecular Pharmacology. 75:1(January 2009) p. 208-217.
Language: English
Date: 2011
YC-1, monoxide-generating enzymes, smooth muscle

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