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

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Suppression of experimental abdominal aortic aneurysms in mice by treatment with pyrrolidine dithiocarbamate, an antioxidant inhibitor of nuclear factor-κB Federico E. Parodi, MD, Dongli Mao, MD, Terri L. Ennis, BS, Michel A. Bartoli, MD, Robert W. Thompson, MD Journal of Vascular Surgery Volume 41, Issue 3, Pages 479-489 (March 2005) DOI: 10.1016/j.jvs.2004.12.030 Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 1 Extent of aortic dilatation. C57BL/6 mice were subjected to transient aortic perfusion with elastase to induce aneurysmal degeneration and were treated every 48 hours with either saline or pyrrolidine dithiocarbamate (PDTC). A, Aortic diameter (AD) measurements were obtained before (AD Pre) and immediately after (AD Post) elastase perfusion; final measurements were obtained on day 14 (AD Final). Data shown represent the mean ± SEM (median values are shown in parentheses). Statistical comparisons between groups were performed with the nonparametric Mann-Whitney U test. B-D, The extent of aortic dilatation immediately after elastase perfusion (B), during the interval between elastase perfusion and death on day 14 (C), and the overall extent of dilatation (D) were each calculated as percentile changes in AD. Data shown represent the mean ± SEM. Statistical comparisons between groups were performed with the nonparametric Mann-Whitney U test (AAA, Threshold for definition of aortic aneurysm; NS, not significant). Journal of Vascular Surgery 2005 41, 479-489DOI: (10.1016/j.jvs.2004.12.030) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 2 Aortic wall structure. Representative micrographs of aortic wall cross sections taken from normal (unperfused) aorta and aortas from mice 14 days after elastase perfusion and treatment with either saline (control) or pyrrolidine dithiocarbamate (PDTC). All sections were stained with Verhoeff-van Gieson, with low-power views (20×) shown on the left and high-power views (100×) shown on the right. A, Normal aorta. B, Day 14 after elastase; saline controls. C, Day 14 after elastase; PDTC treatment. D and E, Histologic sections were scored for the extent of aortic wall inflammation (D) and the integrity of aortic elastin (E) on a five-point scale, by four different examiners unaware of the treatment groups. Data represent the mean ± SEM of histologic scores for three different animals in each group. Comparisons were made with the unpaired (two-tailed) Student t test. Journal of Vascular Surgery 2005 41, 479-489DOI: (10.1016/j.jvs.2004.12.030) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 3 Aortic wall nuclear factor-κB (NF-κB), activator protein (AP)-1, and metalloproteinase (MMP) activities. A and B, Gel-shift assays for NF-κB (A) and AP-1 (B). DNA-binding activities were performed with nuclear protein extracts from normal aorta and aortas from mice 14 days after elastase perfusion and treatment with either saline or pyrrolidine dithiocarbamate (PDTC). Control incubations included an excess of unlabeled DNA probe (competitor) and supershifts with antibodies recognizing p65 for NF-κB or c-Fos for AP-1 (arrows). C, Gelatin zymograms performed with total protein extracts showing increased proteinase activity corresponding to MMP-2 and MMP-9 14 days after elastase perfusion in saline-treated controls, but showing diminished MMP activities in animals treated with PDTC (triplicate samples shown). D, Scanning densitometry of bands corresponding to MMP-9 and MMP-2 in gelatin zymograms, demonstrating a significant reduction in the amount of MMP-9 activity in aortic extracts from PDTC-treated mice compared with saline-treated controls. Data shown represent the mean ± SEM (n = 3 for each group). Statistical comparisons were made with one-way analysis of variance with the Student-Newman-Keuls multiple comparisons test (*P < .05 vs normal aorta and †P < .05 vs PDTC-treated group). E, Gelatin zymograms containing MMP-2 and MMP-9 activities (aortic extracts from day 14 saline-treated mice) were incubated in vitro with substrate buffers containing varying concentrations of PDTC; they demonstrated no direct inhibition of gelatinase activities. Journal of Vascular Surgery 2005 41, 479-489DOI: (10.1016/j.jvs.2004.12.030) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 4 Aortic tissue and serum cytokine levels. Interleukin-1β and interleukin-6 concentrations were measured by enzyme-linked immunosorbent assay in aortic tissue extracts (A and B) and serum (C and D) for normal (unperfused) mice and mice treated with either saline or pyrrolidine dithiocarbamate (PDTC) for 14 days after elastase perfusion. Data shown represent the mean ± SEM (n = 5 for all groups). Statistical comparisons were made with one-way analysis of variance with the Bonferroni multiple comparisons test (*P < .05 vs normal and †P < .05 vs day 14 saline-treated controls). Journal of Vascular Surgery 2005 41, 479-489DOI: (10.1016/j.jvs.2004.12.030) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions