Orally administered dipeptidyl peptidase-4 inhibitor (alogliptin) prevents abdominal aortic aneurysm formation through an antioxidant effect in rats

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Orally administered dipeptidyl peptidase-4 inhibitor (alogliptin) prevents abdominal aortic aneurysm formation through an antioxidant effect in rats Wulan Bao, MD, Keisuke Morimoto, MD, Tomomi Hasegawa, MD, PhD, Naoto Sasaki, MD, PhD, Tomoya Yamashita, MD, PhD, Kenichi Hirata, MD, PhD, Yutaka Okita, MD, PhD, Kenji Okada, MD, PhD Journal of Vascular Surgery Volume 59, Issue 4, Pages 1098-1108 (April 2014) DOI: 10.1016/j.jvs.2013.04.048 Copyright © 2014 Society for Vascular Surgery Terms and Conditions

Fig 1 A, Immunohistochemical staining of aortic walls at day 7. Sections were stained with CD26 antibody (upper panels) and CD68 antibody (lower panels) in the control group (group C), and the low-dose (LD) and high-dose (HD) groups. The arrowheads indicate positive cells (scale bar = 100 μm). B, Messenger RNA expression of CD26 at day 7 in the normal native aorta (normal) and aneurysm wall in the control group that received water (group C). Statistical analysis was done using the Student t-test. ∗P < .001 vs normal. The range bar shows the standard deviation. Journal of Vascular Surgery 2014 59, 1098-1108DOI: (10.1016/j.jvs.2013.04.048) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

Fig 2 A, Aneurysm formation of abdominal aorta at 28 days in each group. Rats in the control group (group C) received water, rats in the low-dose group (group LD) received 1 mg/kg/d alogliptin, and rats in the high-dose group (group HD) received 3 mg/kg/d alogliptin. B, Dilatation ratio in each group. ∗P < .02 group C vs HD. The range bar shows the standard deviation. Journal of Vascular Surgery 2014 59, 1098-1108DOI: (10.1016/j.jvs.2013.04.048) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

Fig 3 Histologic findings of abdominal aortic aneurysm at day 28. Sections were stained with (A) hematoxylin and eosin and (B) elastica von Gieson stain in each group (upper panels: original magnification, ×40; scale bar = 300 μm; lower panels: original magnification, ×400; scale bar = 100 μm). C, Quantitative analysis of elastin content is shown. Data are expressed as mean ± standard deviation (range bars) for six rats per group. Group C, Rats received water; group HD, rats received high-dose alogliptin (3 mg/kg/d); group LD, rats received low-dose alogliptin (1 mg/kg/d); normal, normal native aorta, Statistical analysis was by one-way analysis of variance with post hoc Games-Howell test. ∗P < .0001 vs all other groups. Journal of Vascular Surgery 2014 59, 1098-1108DOI: (10.1016/j.jvs.2013.04.048) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

Fig 4 A, Reactive oxygen species expression stained with dihydroethidium in aneurysm walls at day 7 is shown in the lower panels (original magnification, ×400), whereas the upper panels show correspondent hematoxylin and eosin staining in each group. B, Reactive oxygen species expression in aneurysm walls at day 28 is shown (original magnification, ×400; scale bar = 100 μm). C, The mean fluorescence in a high-power field. All data are expressed as mean ± standard deviation (range bars) for six rats per group. Statistical analysis was by one-way analysis of variance with post hoc Games-Howell test. ∗P < .01 vs all other groups on day 7, ∗P < .01 group C vs HD on day 28. Group C, rats received water; group HD, rats received high-dose alogliptin (3 mg/kg/d); group LD, rats received low-dose alogliptin (1 mg/kg/d); normal, normal native aorta. Journal of Vascular Surgery 2014 59, 1098-1108DOI: (10.1016/j.jvs.2013.04.048) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

Fig 5 A, Immunostaining of 8-hydroxydeoxyguanosine (8-OHdG)-positive cells in aneurysm walls at day 7 is shown (original magnification, ×400; scale bar = 100 μm). B, The number of 8-OHdG cells was counted in a high-power field. All data are expressed as mean ± standard deviation (range bars) for six rats per group. Statistical analysis was by one-way analysis of variance with post hoc Games-Howell test. ∗P < .0001 vs all other groups. Group C, rats received water; group HD, rats received high-dose alogliptin (3 mg/kg/d); group LD, rats received low-dose alogliptin (1 mg/kg/d); normal, normal native aorta. Journal of Vascular Surgery 2014 59, 1098-1108DOI: (10.1016/j.jvs.2013.04.048) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

Fig 6 A, Messenger RNA expression of matrix metalloproteinase (MMP)-2 and MMP-9 in the aneurysm wall at day 7, with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the housekeeping gene. ∗P < .01 vs group C. B, Gelatin zymography demonstrates gelatinolytic activity of MMP-2 and MMP-9. C, Densitometric analysis of MMP-2 (left), Pro-MMP (middle) and MMP-9 (right) activities. All data are expressed as mean ± standard deviation for six rats per group. Statistical analysis was by one-way analysis of variance with post hoc Games-Howell test. ∗P < .01 vs group C. Group C, rats received water as the control; group HD, rats received high-dose alogliptin (3 mg/kg/d); group LD, rats received low-dose alogliptin (1 mg/kg/d); normal, normal native aorta. Journal of Vascular Surgery 2014 59, 1098-1108DOI: (10.1016/j.jvs.2013.04.048) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

Fig 7 A, Aneurysm formation in the abdominal aorta at 7 days in the saline group. B and C, Histologic findings of abdominal aorta at day 7 in the saline group. Sections were stained with hematoxylin and eosin (H&E; B) and elastica von Gieson (EVG; C) (original magnification, ×400). D, Reactive oxygen species expression is shown in aortic walls at day 7 in the saline group (original magnification, ×400). Journal of Vascular Surgery 2014 59, 1098-1108DOI: (10.1016/j.jvs.2013.04.048) Copyright © 2014 Society for Vascular Surgery Terms and Conditions