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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1373.)
© 2001 American Heart Association, Inc.

Thrombosis

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

From the Department of Molecular Biology and Applied Physiology (M.N., K.T., T. Kitomuro, S.S.) and the First Department of Internal Medicine (T. Komaru, M.F., H.S., K. Sato, K. Shirato), Tohoku University School of Medicine, Sendai, Japan; the Department of Biochemical Genetics (T.Y.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; and the Department of Biochemistry (M.S.), School of Medicine, Keio University, Tokyo, Japan.

Correspondence to Shigeki Shibahara, Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. E-mail shibahar{at}mail.cc.tohoku.ac.jp

Abstract—— Heme oxygenase-1 (HO-1) catalyzes the regiospecific oxidative degradation of heme to biliverdin IX, iron, and carbon monoxide. Biliverdin IX is subsequently reduced to bilirubin IX 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 IX 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 anti-bilirubin-IX monoclonal antibody, 24G7, demonstrated accumulation of bilirubin IX in foam cells, indicating that heme is actually degraded in atherosclerotic lesions. Remarkably, bilirubin IX, 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 IX in foam cells, suggesting a role of HO-1 induction in the modulation of macrophage activation in atherosclerosis.

Key Words: cholesterol • atherosclerosis • foam cells • heme oxygenase 1 • bilirubin IX

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