Published online before print May 10, 2007, doi: 10.1161/CIRCRESAHA.107.151720
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Submitted on October 31, 2006
Revised on April 24, 2007
Accepted on April 30, 2007
Heme Oxygenase-1 Expression in Macrophages Plays a Beneficial Role in Atherosclerosis
Luz D. Orozco ;
From the Department of Medicine, Division of Cardiology (L.D.O., B.B., X.W., M.M.W., J.W., Z.S., D.S., A.J.L., J.A.A.), David Geffen School of Medicine at UCLA, Los Angeles, Calif; and the Department of Medicine (M.H.K., J.D., S.B., A.A.), Nephrology Research and Training Center, University of Alabama at Birmingham.
* To whom correspondence should be addressed. E-mail: JAraujo{at}mednet.ucla.edu.
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.
Key words: heme oxygenase-1 • atherosclerosis • macrophages • oxidative stress • inflammation
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