Evidence for a role of macrophage migration inhibitory factor in vascular disease.
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.


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.
Chen
Zhiping
Z
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA.
Sakuma
Masashi
M
Zago
Alexandre C
AC
Zhang
Xiaobin
X
Shi
Can
C
Leng
Lin
L
Mizue
Yuka
Y
Bucala
Richard
R
Simon
Daniel
D
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001161:Arteriosclerosis / Q000235:genetics; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000293:injuries / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D051381:Rats; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology; D014657:Vasculitis / Q000503:physiopathology* / Q000517:prevention & control
D000911:Antibodies, Monoclonal; D016895:Culture Media, Serum-Free; D008263:Macrophage Migration-Inhibitory Factors; D011506:Proteins; D011973:Receptors, LDL; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse