Suppression of experimental abdominal aortic aneurysms in mice by treatment with pyrrolidine dithiocarbamate, an antioxidant inhibitor of nuclear factor-κB

Federico E. Parodi, Dongli Mao, Terri L. Ennis, Michel A. Bartoli, Robert W. Thompson

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

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)-κB 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-κB. 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-κB 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 1β 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-κB and activator protein 1 transcription factor activities, reduced expression of proinflammatory cytokines, and suppression of MMP-9. NF-κB is therefore a potentially important therapeutic target for the suppression of aneurysmal degeneration. Clinical Relevance: 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-κB. In this mouse model, treatment with pyrrolidine dithiocarbamate (a pharmacologic inhibitor of NF-κB) acted to suppress MMP-9 and aneurysm development. It is hoped that treatment strategies that target NF-κB may eventually be shown to suppress the growth of small aortic aneurysms in patients.

Original languageEnglish
Pages (from-to)479-489
Number of pages11
JournalJournal of Vascular Surgery
Volume41
Issue number3
DOIs
StatePublished - Mar 2005

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