Author + information
- Received August 16, 2011
- Revision received October 5, 2011
- Accepted October 11, 2011
- Published online January 10, 2012.
- Aloke V. Finn, MD⁎,⁎ (, )
- Masataka Nakano, MD†,
- Rohini Polavarapu, BA⁎,
- Vinit Karmali, MA⁎,
- Omar Saeed, MD⁎,
- XiaoQing Zhao, PhD†,
- Saami Yazdani, PhD†,
- Fumiyuki Otsuka, MD†,
- Talina Davis⁎,
- Anwer Habib, MD⁎,
- Jagat Narula, MD, PhD‡,
- Frank D. Kolodgie, PhD† and
- Renu Virmani, MD†
- ↵⁎Reprint requests and correspondence:
Dr. Aloke V. Finn, Emory University Hospital Midtown, 550 Peachtree Street NE, Atlanta, Georgia 30307
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.
This study was supported by the Carlyle Fraser Heart Center, CVPath Inc. and the National Institutes of Health grant RO1 HL096970-01A. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. Edward A. Fisher, MD, served as Guest Editor for this paper.
- Received August 16, 2011.
- Revision received October 5, 2011.
- Accepted October 11, 2011.
- American College of Cardiology Foundation