Suppression of experimental abdominal aortic aneurysms in mice by treatment with pyrrolidine dithiocarbamate, an antioxidant inhibitor of nuclear factor-kappaB.
OBJECTIVE
Proinflammatory cytokines and matrix metalloproteinases (MMPs) are prominent mediators of the connective tissue destruction that characterizes abdominal aortic aneurysms (AAAs), and nuclear factor (NF)-kappaB is a cytokine-responsive transcription factor that promotes macrophage MMP expression. The purpose of this study was to determine whether aneurysmal degeneration is influenced by pyrrolidine dithiocarbamate (PDTC), a pharmacologic inhibitor of NF-kappaB.


METHODS
Adult male C57BL/6 mice underwent transient elastase perfusion of the abdominal aorta to induce the development of AAAs. Animals were treated every 48 hours by intraperitoneal injection with either saline (n = 34) or PDTC 20 mg/kg (n = 49). Aortic diameter (AD) measurements were used to determine the extent of aortic dilatation before and immediately after elastase perfusion and again at day 14.


RESULTS
All saline-treated mice developed AAAs associated with mononuclear inflammation and destruction of medial elastin (overall increase in AD, mean +/- SEM, 169.1% +/- 7.5%). In contrast, the incidence of AAAs was only 63% in PDTC-treated mice, with a reduction in the overall increase in AD to 109.8% +/- 4.2% ( P < .0001 vs saline), decreased inflammation, and structural preservation of aortic wall connective tissue. Although aneurysm development in saline-treated mice was associated with a marked increase in aortic tissue NF-kappaB and activator protein 1 DNA-binding activities, both activities were substantially reduced in PDTC-treated animals. PDTC-treated mice also exhibited significantly lower serum and aortic wall concentrations of interleukin 1beta and interleukin 6, as well as lower amounts of aortic wall MMP-9, as compared with saline-treated controls.


CONCLUSIONS
Treatment with PDTC inhibits elastase-induced experimental AAAs in the mouse, along with suppression of aortic wall NF-kappaB and activator protein 1 transcription factor activities, reduced expression of proinflammatory cytokines, and suppression of MMP-9. NF-kappaB is therefore a potentially important therapeutic target for the suppression of aneurysmal degeneration.


CONCLUSIONS
Development and progression of human AAAs is associated with inflammation and enzymatic degradation of connective tissue proteins. MMP-9 is one of the enzymes involved in aneurysm disease, and its production may be induced in part by activation of the transcription factor NF-kappaB. In this mouse model, treatment with pyrrolidine dithiocarbamate (a pharmacologic inhibitor of NF-kappaB) acted to suppress MMP-9 and aneurysm development. It is hoped that treatment strategies that target NF-kappaB may eventually be shown to suppress the growth of small aortic aneurysms in patients.
Parodi
Federico E
FE
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, One Barnes-Jewish Hospital Plaza, St. Louis, MO 63110, USA.
Mao
Dongli
D
Ennis
Terri L
TL
Bartoli
Michel A
MA
Thompson
Robert W
RW
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D024202:Electrophoretic Mobility Shift Assay; D007375:Interleukin-1 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000627:therapeutic use*; D013859:Thiocarbamates / Q000627:therapeutic use*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D018808:Transcription Factor AP-1; C020972:pyrrolidine dithiocarbamic acid; D020780:Matrix Metalloproteinase 9