Increased expression of heme oxygenase-1 and bilirubin accumulation in foam cells of rabbit atherosclerotic lesions.
Heme oxygenase-1 (HO-1) catalyzes the regiospecific oxidative degradation of heme to biliverdin IXalpha, iron, and carbon monoxide. Biliverdin IXalpha is subsequently reduced to bilirubin IXalpha 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 IXalpha 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-IXalpha monoclonal antibody, 24G7, demonstrated accumulation of bilirubin IXalpha in foam cells, indicating that heme is actually degraded in atherosclerotic lesions. Remarkably, bilirubin IXalpha, 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 IXalpha in foam cells, suggesting a role of HO-1 induction in the modulation of macrophage activation in atherosclerosis.
Nakayama
M
M
Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan.
Takahashi
K
K
Komaru
T
T
Fukuchi
M
M
Shioiri
H
H
Sato Ki
Kitamuro
T
T
Shirato
K
K
Yamaguchi
T
T
Suematsu
M
M
Shibahara
S
S
D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism*; D001663:Bilirubin / Q000096:biosynthesis*; D005487:Foam Cells / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D006937:Hypercholesterolemia / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits
D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D001663:Bilirubin