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Research ArticleArticle

Differential Effects of Heme Oxygenase Isoforms on Heme Mediation of Endothelial Intracellular Adhesion Molecule 1 Expression

Frank A. D. T. G. Wagener, Jean-Louis da Silva, Tim Farley, Theo de Witte, Attallah Kappas and Nader G. Abraham
Journal of Pharmacology and Experimental Therapeutics October 1999, 291 (1) 416-423;
Frank A. D. T. G. Wagener
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Jean-Louis da Silva
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Tim Farley
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Theo de Witte
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Attallah Kappas
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Nader G. Abraham
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Abstract

Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme; the latter generates pro-oxidant products, including free radicals. Two HO isozymes, the products of distinct genes, have been described; HO-1 is the inducible isoform, whereas HO-2 is suggested to be constitutively expressed. We studied the inducing effect of several metal compounds (CoCl2, stannic mesoporphyrin, and heme) on HO activity. Additionally, we studied HO-1 expression in experimental models of adhesion molecule expression produced by heme in endothelial cells, and the relationship of HO-1 expression to the induced adhesion molecules. Flow cytometry analysis showed that heme induces intracellular adhesion molecule 1 (ICAM-1) expression in a concentration (10–100 μM)- and time (1–24 h)-dependent fashion in human umbilical vein endothelial cells. Pretreatment with stannic mesoporphyrin, an inhibitor of HO activity, caused a 2-fold increase in heme-induced ICAM-1 expression. In contrast, HO induction by CoCl2 decreased heme-induced ICAM-1 expression by 33%. To examine the contribution of HO-1 and HO-2 to endothelial HO activity, specific antisense oligonucleotides (ODNs) of each isoform were tested for their specificity to inhibit HO activity in cells exposed to heme. Endothelial cells exposed to heme elicited increased HO activity, which was prevented (70%) by HO-1 antisense ODNs. HO-2 antisense ODN inhibited heme-induced HO activity by 21%. Addition of HO-1 antisense ODNs prevented heme degradation and resulted in elevation of microsomal heme. Western blot analysis showed that HO-1 antisense ODNs selectively inhibited HO-1 protein and failed to inhibit HO-2 protein. Incubation of endothelial cells with HO-1 antisense enhanced heme-dependent increase of ICAM-1. In contrast, addition of HO-2 antisense to endothelial cells failed to increase adhesion molecules. The role of glutathione, an important antioxidant, was examined on heme-induced ICAM-1 expression. Endothelial cells pretreated with a glutathione precursor, N-acetylcysteine, or glutathione ester, showed a decrease in heme-induced ICAM-1 expression of 37 and 44%, respectively, suggesting that the mechanism of ICAM-1 induction by heme may be partly dependent on the levels of antioxidant. It is possible that amelioration of the heme-induced oxidative stress and expression of ICAM-I is due, in part, to the induction of HO-1 activity. Regulation of HO activity in this manner may have clinical applications.

Footnotes

  • Send reprint requests to: Dr. Nader G. Abraham, Professor of Pharmacology, New York Medical College, Basic Science Building, Department of Pharmacology, Valhalla, NY 10595. E-mail:nader_abraham{at}nymc.edu

  • ↵1 This study was supported by National Institutes of Health Grant HL5-4138 and the Contigney Foundation.

  • ↵2 Present address: Department of Hematology, Academic Hospital, St. Radboud, Nijmegen, the Netherlands.

  • Abbreviations:
    HO
    heme oxygenase
    ICAM-1
    intracellular adhesion molecule 1
    HUVEC
    human umbilical vein endothelial cell
    SnMP
    stannic mesoporphyrin
    NAC
    N-acetylcysteine
    GSH-ET
    l-γ-glutamylglycine ethyl ester
    FITC
    fluorescein isothiocyanate
    LDH
    lactate dehydrogenase
    ODN
    oligonucleotide
    DOTAP
    N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate
    • Received March 17, 1999.
    • Accepted May 26, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 1
1 Oct 1999
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Research ArticleArticle

Differential Effects of Heme Oxygenase Isoforms on Heme Mediation of Endothelial Intracellular Adhesion Molecule 1 Expression

Frank A. D. T. G. Wagener, Jean-Louis da Silva, Tim Farley, Theo de Witte, Attallah Kappas and Nader G. Abraham
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 416-423;

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Research ArticleArticle

Differential Effects of Heme Oxygenase Isoforms on Heme Mediation of Endothelial Intracellular Adhesion Molecule 1 Expression

Frank A. D. T. G. Wagener, Jean-Louis da Silva, Tim Farley, Theo de Witte, Attallah Kappas and Nader G. Abraham
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 416-423;
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