TY - JOUR
T1 - Increased expression of heme oxygenase-1 and bilirubin accumulation in foam cells of rabbit atherosclerotic lesions
AU - Nakayama, Masaharu
AU - Takahashi, Kazuhiro
AU - Komaru, Tatsuya
AU - Fukuchi, Mitsumasa
AU - Shioiri, Hiroki
AU - Sato, Ko Ichi
AU - Kitamuro, Tomomi
AU - Shirato, Kunio
AU - Yamaguchi, Tokio
AU - Suematsu, Makoto
AU - Shibahara, Shigeki
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Bilirubin IXα
KW - Cholesterol
KW - Foam cells
KW - Heme oxygenase 1
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U2 - 10.1161/hq0801.093592
DO - 10.1161/hq0801.093592
M3 - Article
C2 - 11498468
AN - SCOPUS:0035574676
SN - 1079-5642
VL - 21
SP - 1373
EP - 1377
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 8
ER -