Increased expression of heme oxygenase-1 and bilirubin accumulation in foam cells of rabbit atherosclerotic lesions

Masaharu Nakayama, Kazuhiro Takahashi, Tatsuya Komaru, Mitsumasa Fukuchi, Hiroki Shioiri, Ko Ichi Sato, Tomomi Kitamuro, Kunio Shirato, Tokio Yamaguchi, Makoto Suematsu, Shigeki Shibahara

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)


Heme oxygenase-1 (HO-1) catalyzes the regiospecific oxidative degradation of heme to biliverdin IXα, iron, and carbon monoxide. Biliverdin IXα is subsequently reduced to bilirubin IXα by biliverdin reductase. HO-1 expression is induced under various disease conditions, including atherosclerosis, but it is unknown whether HO-1 catalyzes heme breakdown in the regions at risk. Using hypercholesterolemic rabbits fed a cholesterol-enriched diet, we attempted to demonstrate the involvement of HO-1 induction and bilirubin IXα production in atherosclerotic regions. Expression levels of HO-1 mRNA were elevated in the aortas of hypercholesterolemic rabbits. In situ hybridization and immunohistochemistry revealed that mRNA and protein of HO-1 are induced in endothelial cells and foam cells (lipid-filled macrophages) in atherosclerotic lesions. Furthermore, immunohistochemistry with the use of an antibilirubin-IXα monoclonal antibody, 24G7, demonstrated accumulation of bilirubin IXα in foam cells, indicating that heme is actually degraded in atherosclerotic lesions. Remarkably, bilirubin IXα, like HO-1 protein, is predominantly accumulated in the perinuclear regions of foam cells. These results provide the first in vivo evidence of the colocalization of HO-1 and bilirubin IXα in foam cells, suggesting a role of HO-1 induction in the modulation of macrophage activation in atherosclerosis.

Original languageEnglish
Pages (from-to)1373-1377
Number of pages5
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number8
Publication statusPublished - 2001
Externally publishedYes


  • Atherosclerosis
  • Bilirubin IXα
  • Cholesterol
  • Foam cells
  • Heme oxygenase 1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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