Evidence for a role of macrophage migration inhibitory factor in vascular disease
Zhiping Chen1, Masashi Sakuma, Alexandre C Zago
1Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA.
Objective:
Inflammation plays an essential role in atherosclerosis and restenosis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is widely expressed in vascular cells. However, there is no in vivo evidence that MIF participates directly in vascular injury and repair. Therefore, we investigated the effect of MIF blockade on the response to experimental angioplasty in atherosclerosis-susceptible mice.
Methods And Results:
Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDL receptor-deficient mice treated with a neutralizing anti-MIF or isotype control monoclonal antibody. After 7 days and 28 days, intimal and medial sizes were measured and intima/media area ratio (I/M) was calculated. Intimal thickening and I/M were reduced significantly by anti-MIF compared with control antibody. Vascular injury was accompanied by progressive vessel enlargement or "positive remodeling" that was comparable in both treatment groups. MIF blockade was associated with reduced inflammation and cellular proliferation and increased apoptosis after injury.
Conclusions:
Neutralizing MIF bioactivity after experimental angioplasty in atherosclerosis-susceptible mice reduces vascular inflammation, cellular proliferation, and neointimal thickening. Although the molecular mechanisms responsible for these effects are not yet established, these data prompt further research directed at understanding the role of MIF in vascular disease and suggest novel therapeutic interventions for preventing atherosclerosis and restenosis.
Insights
Blocking macrophage migration inhibitory factor (MIF) after angioplasty in mice with atherosclerosis reduced vascular inflammation, cell proliferation, and neointimal thickening, suggesting MIF as a therapeutic target.
Area of Science:
- Vascular Biology
- Immunology
- Cardiovascular Research
Background:
- Inflammation is critical in atherosclerosis and restenosis.
- Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine found in vascular cells.
- In vivo evidence for MIF's role in vascular injury and repair was lacking.
Purpose of the Study:
- To investigate the effect of blocking MIF on the response to experimental angioplasty.
- To assess MIF's direct role in vascular injury and repair processes.
Main Methods:
- Experimental angioplasty was performed on atherosclerosis-susceptible mice (LDL receptor-deficient).
- Mice received either a neutralizing anti-MIF antibody or an isotype control antibody.
- Vascular remodeling, intimal thickening, inflammation, cellular proliferation, and apoptosis were measured at 7 and 28 days post-angioplasty.
Main Results:
- Anti-MIF treatment significantly reduced intimal thickening and the intima/media area ratio compared to controls.
- MIF blockade led to decreased vascular inflammation and cellular proliferation.
- Increased apoptosis was observed in vessels treated with anti-MIF after injury.
Conclusions:
- Neutralizing MIF bioactivity effectively reduces vascular inflammation, proliferation, and neointimal thickening post-angioplasty in susceptible mice.
- These findings highlight MIF's role in vascular disease.
- Targeting MIF may offer novel therapeutic strategies for preventing atherosclerosis and restenosis.
