Neutralization of interleukin-18 inhibits neointimal formation in a rat model of vascular injury.
BACKGROUND
Studies in humans and animal models suggest that interleukin-18 (IL-18) plays a crucial role in vascular pathologies. IL-18 is a predictor of cardiovascular death in angina and is involved in atherotic plaque destabilization. Higher IL-18 plasma levels also are associated with restenosis after coronary artery angioplasty performed in patients with acute myocardial infarction. We investigated the effective role of IL-18 in neointimal formation in a balloon-induced rat model of vascular injury.


RESULTS
Endothelial denudation of the left carotid artery was performed by use of a balloon embolectomy catheter. Increased expression of IL-18 and IL-18Ralpha/beta mRNA was detectable in carotid arteries from days 2 to 14 after angioplasty. The active form of IL-18 was highly expressed in injured arteries. Strong immunoreactivity for IL-18 was detected in the medial smooth muscle cells at days 2 and 7 after balloon injury and in proliferating/migrating smooth muscle cells in neointima at day 14. Moreover, serum concentrations of IL-18 were significantly higher among rats subjected to vascular injury. Treatment with neutralizing rabbit anti-rat IL-18 immunoglobulin G significantly reduced neointimal formation (by 27%; P < 0.01), reduced the number of proliferating cells, and inhibited interferon-gamma, IL-6, and IL-8 mRNA expression and nuclear factor-kappaB activation in injured arteries. In addition, in vitro data show that IL-18 affects smooth muscle cell proliferation.


CONCLUSIONS
These results identify a critical role for IL-18 in neointimal formation in a rat model of vascular injury and suggest a potential role for IL-18 neutralization in the reduction of neointimal development.
Maffia
Pasquale
P
Department of Experimental Pharmacology, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy. pamaffia@unina.it
Grassia
Gianluca
G
Di Meglio
Paola
P
Carnuccio
Rosa
R
Berrino
Liberato
L
Garside
Paul
P
Ianaro
Angela
A
Ialenti
Armando
A
D000199:Actins / Q000032:analysis; D000818:Animals; D021721:Balloon Occlusion / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000503:physiopathology*; D002339:Carotid Arteries / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D020212:Carotid Artery Injuries / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007074:Immunoglobulin G / Q000494:pharmacology; D007371:Interferon-gamma / Q000032:analysis / Q000235:genetics / Q000502:physiology; D020382:Interleukin-18 / Q000032:analysis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D016209:Interleukin-8 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology; D016328:NF-kappa B / Q000032:analysis / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D017539:Tunica Intima / Q000473:pathology / Q000503:physiopathology*
D000199:Actins; D007074:Immunoglobulin G; D007371:Interferon-gamma; D020382:Interleukin-18; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; C498862:Acta2 protein, rat