Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques

AV Finn, M Nakano, R Polavarapu, V Karmali… - Journal of the American …, 2012 - jacc.org
AV Finn, M Nakano, R Polavarapu, V Karmali, O Saeed, XQ Zhao, S Yazdani, F Otsuka
Journal of the American College of Cardiology, 2012jacc.org
Objectives: The purpose of this study was to examine selective macrophage differentiation
occurring in areas of intraplaque hemorrhage in human atherosclerosis. Background:
Macrophage subsets are recognized in atherosclerosis, but the stimulus for and importance
of differentiation programs remain unknown. Methods: We used freshly isolated human
monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage
differentiation in response to hemorrhage. Results: Macrophages characterized by high …
Objectives
The purpose of this study was to examine selective macrophage differentiation occurring in areas of intraplaque hemorrhage in human atherosclerosis.
Background
Macrophage subsets are recognized in atherosclerosis, but the stimulus for and importance of differentiation programs remain unknown.
Methods
We used freshly isolated human monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage differentiation in response to hemorrhage.
Results
Macrophages characterized by high expression of both mannose and CD163 receptors preferentially exist in atherosclerotic lesions at sites of intraplaque hemorrhage. These hemoglobin (Hb)-stimulated macrophages, M(Hb), are devoid of neutral lipids typical of foam cells. In vivo modeling of hemorrhage in the rabbit model demonstrated that sponges exposed to red cells showed an increase in mannose receptor–positive macrophages only when these cells contained Hb. Cultured human monocytes exposed to Hb:haptoglobin complexes, but not interleukin-4, expressed the M(Hb) phenotype and were characterized by their resistance to cholesterol loading and up-regulation of ATP-binding cassette (ABC) transporters. M(Hb) demonstrated increased ferroportin expression, reduced intracellular iron, and reactive oxygen species (ROS). Degradation of ferroportin using hepcidin increased ROS and inhibited ABCA1 expression and cholesterol efflux to apolipoprotein A-I, suggesting reduced ROS triggers these effects. Knockdown of liver X receptor alpha (LXRα) inhibited ABC transporter expression in M(Hb) and macrophages differentiated in the antioxidant superoxide dismutase. Last, LXRα luciferase reporter activity was increased in M(Hb) and significantly reduced by overnight treatment with hepcidin. Collectively, these data suggest that reduced ROS triggers LXRα activation and macrophage reverse cholesterol transport.
Conclusions
Hb is a stimulus for macrophage differentiation in human atherosclerotic plaques. A decrease in macrophage intracellular iron plays an important role in this nonfoam cell phenotype by reducing ROS, which drives transcription of ABC transporters through activation of LXRα. Reduction of macrophage intracellular iron may be a promising avenue to increase macrophage reverse cholesterol transport.
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