Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice

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.

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…Foam cells produce a microenvironment abundant with ROS, which amplifies the retention of oxidized lipids such as oxLDL in the vascular wall. HO-1 expression within foam cells attenuates their production of pro-inflammatory cytokines and downregulates the expression of lipid SRs (73,128).…”

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

“…Induction of HO-1 by chemical inducers results in the reduction of atherosclerotic lesions in LDL-receptor knockout mice and prevents transplant arteriosclerosis in mouse cardiac allografts (Hancock et al, 1998;Ishikawa et al, 2001). Similarly, adenovirus-mediated transfer of HO-1 to arteries significantly attenuates the development of atherosclerosis in apoE null mice and graft arteriosclerosis in a rat model of chronic allogeneic aorta rejection (Juan et al, 2001;Bouche et al, 2002).…”

Potential role of heme oxygenase-1 in the progression of rat adjuvant arthritis

“…Protection by HO-1 can be of relevance during endotoxemia, 13 liver failure 14 or lung hyperoxia. 15 HO-1 also prevents atherogenesis 16 and myocardial injury after ischemia-reperfusion. 17 Interestingly, metabolites derived from HO-1 activity suppress T-cell proliferation and improve cardiac allograft survival.…”