Heme Oxygenase-1 Expression in Macrophages Plays a Beneficial Role in Atherosclerosis

Abstract

Abstract-Heme oxygenase (HO-1) is the rate-limiting enzyme in the catabolism of heme, which leads to the generation of biliverdin, iron, and carbon monoxide. It has been shown to have important antioxidant and antiinflammatory properties that result in a vascular antiatherogenic effect. To determine whether HO-1 expression in macrophages constitutes a significant component of the protective role in atherosclerosis, we evaluated the effect of decreased or absent HO-1 expression in peritoneal macrophages on oxidative stress and inflammation in vitro, and the effect of complete deficiency of HO-1 expression in macrophages in atherosclerotic lesion formation in vivo. We found that compared with HO-1 ϩ/ϩ controls, peritoneal macrophages from HO-1 Ϫ/Ϫ and HO-1 ϩ/Ϫ mice exhibited (1) increased reactive oxygen species (ROS) generation, (2) increased proinflammatory cytokines such as monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6), and (3) increased foam cell formation when treated with oxLDL, attributable in part to increased expression of scavenger receptor A (SR-A). Bone marrow transplantation experiments performed in lethally irradiated LDL-R null female mice, reconstituted with bone marrow from HO-1 Ϫ/Ϫ versus HO-1 ϩ/ϩ mice, revealed that HO-1 Ϫ/Ϫ reconstituted animals exhibited atherosclerotic lesions with a greater macrophage content as evaluated by immunohistochemistry and planimetric assessment. We conclude that HO-1 expression in macrophages constitutes an important component of the antiatherogenic effect by increasing antioxidant protection and decreasing the inflammatory component of atherosclerotic lesions.

Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1

“…Heme oxygenase-1 (HO-1), the key enzyme in heme catabolism, has been reported to display several benefi cial effects in atherosclerosis-related CVDs (14)(15)(16). In addition, emerging evidence suggests that HO-1 participates in the protective effects of Tan in several cell types ( 17,18 ).…”

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

“…Recently, a more complete understanding of this process has implicated HO-1 expression within MP as an effector of atheroprotection (128). Microenvironmental heterogeneity in atherosclerotic plaques drives the development of distinct macrophage subpopulations that differentially effect the progression of atherosclerotic disease based on their effector functions (30).…”

“…In the plaque's necrotic core, oxidized LDL (oxLDL) is bound to scavenger receptors including CD36, SR-A/B, and LOX-1 on macrophages (163 (162). However, when HO-1-deficient macrophages are treated with oxLDL, generation of ROS is amplified and secretion of pro-inflammatory IL-6, MCP-1, and the IL-8 homologue, KC is increased (128). Thus, HO-1 expression in macrophages may render them resistant to foam cell formation and to production of pro-inflammatory mediators that exacerbate atherogenesis and plaque progression.…”

“…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).…”

CXCL4-Induced Macrophages: A Novel Therapeutic Target in Human Atherosclerosis?

“…Binding of the ligand to CD163 results in upregulation of heme oxygenase-1 (Schaer et al 2006). Heme oxygenase-1 (and specifically heme oxygenase-1 expressed in bone marrow-derived cells like monocytes and monocyte-derived macrophages) is thought to be atheroprotective as demonstrated in several mouse models (Juan et al 2001, Orozco et al 2007, Yet et al 2003. Further experiments studying gene and protein expression in freshly isolated blood monocytes and macrophage induced either by MCSF or CXCL4 confirmed the significant differences.…”