Nf-kappab and AP-1 activation is associated with late lumen loss after porcine coronary angioplasty and antiproliferative beta-irradiation.
OBJECTIVE
Despite the success of antiproliferative therapies, restenosis remains a common problem after percutaneous transluminal coronary angioplasty (PTCA). Longer-term clinical results of brachytherapy (intracoronary radiation), the lack of long-term clinical results after implantation of drug eluting stents, and the occurrence of late thrombosis after both procedures leave room for skepticism. Neointimal proliferation is not substantially inhibited at late time points after brachytherapy, and late lumen loss with a "catch-up" proliferation can occur. We hypothesized that the transcription factors nuclear factor-{kappa}B (NF-kappaB) and activator protein-1 (AP-1) are involved in these processes. We addressed the role of these mediators in a porcine model of coronary restenosis.


METHODS
Thirty-nine pigs underwent PTCA in two major coronary arteries. One of the two balloon-injured arteries was randomly assigned to receive immediate 20 Gy beta-irradiation (Brachy group) using a noncentered source train ((90)Sr/Y Beta-Cath, Novoste). Animals were sacrificed after 1 day, 14 days, or 28 days. Proliferating cells were labeled prior to euthanasia.


RESULTS
At late time points, lumen area was significantly smaller and the inflammatory response was more pronounced in the Brachy group than in the PTCA group. These findings coincided with sustained activation of MMP-9 and transcription factors like NF-kappaB and AP-1. Initially, cell proliferation was reduced in the Brachy group; however, at late time points, differences between the two treatment groups were no longer significant.


CONCLUSIONS
Brachytherapy initially inhibits cell proliferation; however, cellular and molecular inflammatory processes (e.g. activation of NF-kappaB) are enhanced within the arterial wall. This proinflammatory side effect may be responsible for the observed delayed proliferation and the resulting lumen loss.
Deiner
Carolin
C
Institute of Veterinary Physiology, Faculty of Veterinary Medicine, FU Berlin, Berlin, Germany.
Shagdarsuren
Erdenechimeg
E
Schwimmbeck
Peter L
PL
Rosenthal
Peter
P
Loddenkemper
Christoph
C
Rauch
Ursula
U
Pauschinger
Matthias
M
Dietz
Rainer
R
Schultheiss
Heinz-Peter
HP
Dechend
Ralf
R
Pels
Klaus
K
D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D001610:Beta Particles; D001918:Brachytherapy; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003327:Coronary Disease / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy; D023903:Coronary Restenosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D023421:Models, Animal; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism*; D011897:Random Allocation; D012644:Selenium Radioisotopes; D034421:Sus scrofa; D013552:Swine; D013601:T-Lymphocytes / Q000473:pathology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000032:analysis / Q000378:metabolism*
D016328:NF-kappa B; D012644:Selenium Radioisotopes; D018808:Transcription Factor AP-1; D020780:Matrix Metalloproteinase 9