Regular Article
The Antioxidant Defense Protein Ferritin Is a Novel and Specific Target for Pentaerithrityl Tetranitrate in Endothelial Cells

https://doi.org/10.1006/bbrc.1999.0941Get rights and content

Abstract

The organic nitrate pentaerithrityl tetranitrate (PETN) is known to exert long-term antioxidant and antiatherogenic effects by as yet unidentified mechanisms. In porcine aortic endothelial cells, a 24 h incubation with PETN (1–100 μM) or its metabolite pentaerithrityl trinitrate (PETriN) increased levels of the antioxidant protein ferritin up to three-fold over basal, whereas isosorbide dinitrate and isosorbide-5-mononitrate were without significant effect under these conditions. PETriN-induced ferritin expression was blocked by the NO scavenger PTIO but remained unaltered in the presence of ODQ, an inhibitor of soluble guanylyl cyclase. 8-Bromo cyclic GMP and dibutyryl cyclic GMP did not influence basal ferritin synthesis. The iron chelator desferrioxamine abolished ferritin induction by PETriN. Our results show that PETN or its active metabolite PETriN induce ferritin synthesis through NO- and iron-dependent but cyclic GMP-independent pathways. Increased activity of ferritin may contribute to, and at least in part explain, the specific antiatherogenic and antioxidant action of PETN.

References (42)

  • G. Kojda et al.

    Eur. J. Pharmacol.

    (1998)
  • G. Balla et al.

    J. Biol. Chem.

    (1992)
  • G. Cairo et al.

    J. Biol. Chem.

    (1995)
  • Y.M. Kim et al.

    FEBS Lett.

    (1995)
  • S. Oberle et al.

    Nitric Oxide.

    (1997)
  • F.B. Lin et al.

    Arch. Biochem. Biophys.

    (1998)
  • H.P. Podhaisky et al.

    FEBS Lett.

    (1997)
  • B. Hinz et al.

    Biochem. Biophys. Res. Commun.

    (1998)
  • T. Akaike et al.

    Methods Enzymol.

    (1996)
  • S. Recalcati et al.

    Blood

    (1998)
  • P.M. Harrison et al.

    Biochim. Biophys. Acta.

    (1996)
  • A.A. Weber et al.

    Eur. J. Pharmacol.

    (1993)
  • H. Schröder et al.

    J. Pharmacol. Exp. Ther.

    (1988)
  • D.G. Harrison et al.

    Circulation

    (1993)
  • M. Feelisch et al.
  • L.A. Crandall et al.

    J. Pharmacol. Exp. Ther.

    (1931)
  • M.G. Bogaert et al.

    Arch. Int. Pharmacodyn. Ther.

    (1968)
  • T. Münzel et al.

    J. Clin. Invest.

    (1995)
  • T. Münzel et al.

    J. Mol. Med.

    (1997)
  • B. Fink et al.

    J. Cardiovasc. Pharmacol.

    (1997)
  • Cited by (62)

    • Chemopreventive effects of standardized papaya leaf fraction on oxidatively stressed human liver cells

      2014, Food Research International
      Citation Excerpt :

      Given that this fraction induced hmox-1 expression, the cytoprotective effect of PE might be mediated by the catabolic products of this enzyme; carbon monoxide, biliverdin and ferritin. All these metabolites possessed antioxidant properties (Oberle, Schwartz, Abate, & Schroder, 1999; Otterbein & Choi, 2000; Yesilkaya, Altinayak, & Korgun, 2000) with anti-apoptotic, anti-proliferative and anti-inflammatory actions (Otterbein, Soares, Yamashita, & Bach, 2003). The other highly transcribed gene, nqo-1, was a metabolic enzyme responsible for the detoxification of xenobiotics and the excretion of reactive metabolites (Iskander & Jaiswal, 2005).

    • Chemopreventive effects of standardized papaya leaf fraction on oxidatively stressed human liver cells

      2014, Food Research International
      Citation Excerpt :

      Given that this fraction induced hmox-1 expression, the cytoprotective effect of PE might be mediated by the catabolic products of this enzyme; carbon monoxide, biliverdin and ferritin. All these metabolites possessed antioxidant properties (Oberle, Schwartz, Abate, & Schroder, 1999; Otterbein & Choi, 2000; Yesilkaya, Altinayak, & Korgun, 2000) with anti-apoptotic, anti-proliferative and anti-inflammatory actions (Otterbein, Soares, Yamashita, & Bach, 2003). The other highly transcribed gene, nqo-1, was a metabolic enzyme responsible for the detoxification of xenobiotics and the excretion of reactive metabolites (Iskander & Jaiswal, 2005).

    • Organic nitrates and nitrate tolerance-state of the art and future developments

      2010, Advances in Pharmacology
      Citation Excerpt :

      At least two of these metabolites (PEDN and PEMN) are present at high-plasma levels and do not induce tachyphylaxis. But even more important could be the induction of protective genes by PETN and its trinitrate such as the heme oxygenase-1 and ferritin in vitro (Gori et al., 2010; Oberle et al., 1999, 2002, 2003) and in vivo (Fig. 11; Daiber & Munzel, 2010a; Schuhmacher et al., 2010; Wenzel et al., 2007b). Via breakdown of porphyrins, HO-1 produces the antioxidant molecule bilirubin (which is formed from biliverdin by biliverdin reductase; Florczyk et al., 2008) and the vasodilator carbon monoxide (CO) (Oberle et al., 2003; Wenzel et al., 2007b).

    • Nitrate tolerance as a model of vascular dysfunction: Roles for mitochondrial aldehyde dehydrogenase and mitochondrial oxidative stress

      2009, Pharmacological Reports
      Citation Excerpt :

      Bilirubin is formed from biliverdin by biliverdin reductase [29]. HO-1 in turn stimulates the expression of a second antioxidant protein, ferritin, by triggering the release of free iron from endogenous heme sources [71]. HO-1 is a highly protective enzymatic system [26].

    View all citing articles on Scopus

    Abbreviations used: GTN, glyceryl trinitrate; ISDN, isosorbide dinitrate; ISMN, isosorbide-5-mononitrate; NO, nitric oxide; ODQ, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one; PETN, pentaerithrityl tetranitrate; PETriN, pentaerithrityl trinitrate; PTIO, phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide

    View full text