Heme arginate pretreatment attenuates pulmonary NF-κB and AP-1 activation induced by hemorrhagic shock via heme oxygenase-1 induction

T. Sasaki, Takatoru Takahashi, H. Shimizu, Y. Toda, H. Morimatsu, M. Takeuchi, M. Yokoyama, R. Akagi, K. Morita

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Hemorrhagic shock followed by resuscitation (HSR) induces oxidative stress that leads to acute lung injury. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, is induced by oxidative stress and is thought to play an important role in the protection from oxidative tissue injuries. We previously demonstrated that HO-1 induction by heme arginate (HA), a strong inducer of HO-1, ameliorated HSR-induced lung injury and inflammation. Cellular redox state is known to modulate the DNA biding activity of the transcription factors; nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). In the present study, we treated rats with HA (30 mg/kg of hemin) 18 h prior to HSR and examined its effect on the DNA binding activity of NF-κB and AP-1 at 1.5 h after HSR. HSR significantly increased the DNA binding activity of NF-κB as well as AP-1, while HA pretreatment markedly attenuated the activities of these transcription factors. In contrast, administration of tin mesoporphyrin, a specific competitive inhibitor of HO activity, to HA-pretreated animals abolished the suppressive effect of HA on the activities of NF-κB and AP-1, and increased these activities to almost the same level as those in HSR animals. Our findings indicate that HA pretreatment can significantly suppress the increased activity of NF-κB and AP-1 induced by HSR by virtue of its ability to induce HO-1. Our findings also suggest that HO-1 induced by HA pretreatment ameliorates HSR-induced lung injury at least in part mediated through the suppression of the activities of these transcription factors.

Original languageEnglish
Pages (from-to)271-274
Number of pages4
JournalMedicinal Chemistry
Volume2
Issue number3
DOIs
Publication statusPublished - May 1 2006

Keywords

  • Activator protein-1
  • Acute lung injury
  • Heme arginate
  • Heme oxygenase-1
  • Hemorrhagic shock
  • Inflammation
  • Nuclear factor-κB
  • Oxidative stress

ASJC Scopus subject areas

  • Drug Discovery

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