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

Luz D. Orozco(University of California, Los Angeles), Matthias Kapturczak(University of California, Los Angeles), Berenice Barajas(University of California, Los Angeles), Xuping Wang(University of California, Los Angeles), Michael M. Weinstein(University of California, Los Angeles), Jack Wong(University of California, Los Angeles), Jessy S. Deshane(University of California, Los Angeles), Subhashini Bolisetty(University of California, Los Angeles), Zory Shaposhnik(University of California, Los Angeles), Diana M. Shih(University of California, Los Angeles), Anupam Agarwal(University of California, Los Angeles), Aldons J. Lusis(University of California, Los Angeles), Jesús A. Araujo(University of California, Los Angeles)
Circulation Research
May 11, 2007
10.1161/circresaha.107.151720
Cited by 189Open Access
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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(+/+) controls, peritoneal macrophages from HO-1(-/-) and HO-1(+/-) 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(-/-) versus HO-1(+/+) mice, revealed that HO-1(-/-) 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.

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