© 2001 American Heart Association, Inc.
Integrative Physiology |
Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice
From the First Department of Internal Medicine (K.I., D.S., Y.M.) and Second Department of Anatomy (K.S.), Fukushima Medical University, Fukushima, Japan; Department of Microbiology and Molecular Pathology (H.I.), Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan; and Departments of Cardiology (A.J.L.) and Microbiology and Molecular Genetics (X.-p.W.), School of Medicine, University of California, Los Angeles, Calif.
Correspondence to Kazunobu Ishikawa, MD, PhD, First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan 960-1295. E-mail kishikaw{at}cc.fmu.ac.jp
Abstract—Heme oxygenase-1 (HO-1) is induced by a variety of conditions associated with oxidative stress. We demonstrated that mildly oxidized LDL markedly induces HO-1 in human aortic endothelial and smooth muscle cell cocultures and that its induction results in the attenuation of monocyte chemotaxis resulting from treatment with mildly oxidized LDL in vitro. To elucidate the role of HO-1 in the development of atherosclerotic lesions in vivo, we modulated HO-1 expression in LDL-receptor knockout mice fed high-fat diets. During 6-week high-fat diet trials, intraperitoneal injections of hemin (H group) or hemin and desferrioxamine (HD group) to induce HO-1, Sn-protoporphyrin IX to inhibit HO-1 (Sn group), and saline as control (C group) were performed. Both the H and HD groups showed significantly less mean atherosclerotic lesions in the proximal aorta compared with the C group, whereas the Sn group showed larger lesion compared with the C group. Modulation of HO expression and HO activities were confirmed by Northern blot analysis and HO activity assay. Immunohistochemical studies revealed significant HO-1 expression in atherosclerotic lesions, where oxidized phospholipids also localized. Major cell types expressing HO-1 were macrophages and foam cells in the lesions. HO modulations affected plasma lipid hydroperoxide (LPO) levels and nitrite/nitrate levels. These results suggest that HO-1, induced under hyperlipidemia, functioned as an intrinsic protective factor against atherosclerotic lesion formation, possibly by inhibiting lipid peroxidation and influencing the nitric oxide pathway.
Key Words: heme oxygenase • LDL-receptor knockout mice • high-fat diet • oxidized LDL • atherosclerosis
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