Controlled release of small interfering RNA targeting midkine attenuates intimal hyperplasia in vein grafts Hiroshi Banno, MD, Yoshifumi Takei, PhD,

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Controlled release of small interfering RNA targeting midkine attenuates intimal hyperplasia in vein grafts Hiroshi Banno, MD, Yoshifumi Takei, PhD, Takashi Muramatsu, PhD, Kimihiro Komori, MD, PhD, Kenji Kadomatsu, MD, PhD Journal of Vascular Surgery Volume 44, Issue 3, Pages 633-641 (September 2006) DOI: 10.1016/j.jvs.2006.04.044 Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 1 Increased midkine (MK) expression in a rabbit vein graft. A, The time course of MK expression in the rabbit vein graft is shown. Protein extracts of grafted veins at the indicated times after operation were subjected to Western blot analysis for MK and β-actin. B, Immunostaining for MK 7 days after operation is shown (upper left and right). A magnified photo of the upper left panel is shown at upper right. The bottom panel shows a control staining without the first antibody of an adjacent section. Bars, 100 μm. Journal of Vascular Surgery 2006 44, 633-641DOI: (10.1016/j.jvs.2006.04.044) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 2 Effects of small interfering RNAs (siRNAs) targeting rabbit midkine (MK) on its expression in cultured cells. A, The full-length rabbit MK complimentary DNA sequence and design of siRNAs targeting rabbit MK are shown. The five siRNAs examined in this study are indicated by bars. B, RK13 cells were transfected with MK siRNAs or Lipofectamine 2000 alone (mock), or not treated (n = 3 dishes). A representative Western blot for MK is shown. The relative densitometric intensities of Western blot bands of MK were calculated and are presented as the average ± SEM in the graph (n = 3). C, Stabilized siRNAs retained inhibitory effects equal to those of the unmodified siRNAs. A Western blot for MK is shown. Journal of Vascular Surgery 2006 44, 633-641DOI: (10.1016/j.jvs.2006.04.044) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 3 Controlled release of small interfering RNA (siRNA) into the grafted vein wall. A, A poor run-off vein graft model with distal branch ligation is depicted. The most inferior branch of the external carotid artery serves as the only outflow for the low-flow graft. CCA, common carotid artery; ECA, external carotid artery; ICA, internal carotid artery; VG, vein graft. B, Successful transfer in vivo was determined by fluorescent photomicrography of atelocollagen with a Cy3-conjugated scrambled siRNA-treated graft 7 days after operation. Low (upper left) and high (lower left) magnifications are shown. The upper right panel shows an adjacent section stained with hematoxylin and eosin. Note the absence of the Cy3 signal (red color) in the graft treated with atelocollagen without siRNA (lower right). The dotted line indicates the internal edge of the vessel. A, atelocollagen; L, indicates lumen. C, The effect of midkine (MK) siRNA on MK expression at 7 days after operation was assessed by Western blot. Relative densitometric densities are shown in the graph (n=3). Journal of Vascular Surgery 2006 44, 633-641DOI: (10.1016/j.jvs.2006.04.044) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 4 Quantification of intimal hyperplasia. A, Representative elastic Van Gieson-stained sections from animals at 4 weeks after operation. Representative photos at low (above) and high (below) magnifications are presented. Arrowheads indicate the internal elastic lamina. Bars, 1 mm. B, The graph shows the intima-media ratio (left) and intimal thickness (right) (n = 5 in each group, *P < .05 by analysis of variance with the Bonferroni post hoc analysis). SCR siRNA, scrambled small interfering RNA; MK, midkine. Journal of Vascular Surgery 2006 44, 633-641DOI: (10.1016/j.jvs.2006.04.044) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 5 Cell proliferation in a grafted vein 14 days after operation. A, Proliferating cell nuclear antigen (PCNA)-immunostained sections of grafts treated with midkine (MK) small interfering RNA (SCR siRNA) (upper panel) and scrambled siRNA (SCR siRNA) (lower panel). High magnification views are shown on the right. The bar graph shows the percentage of PCNA-positive cells in the intima (n = 5, *P < .01). B, Ki-67-immunostained sections of grafts treated with MK siRNA (upper panel) and scrambled siRNA (lower panel).High magnification views are shown on the right. The bar graph shows the percentages of Ki-67-positive cells in the intima (n=5, *P < 0.001). Bars, 200 μm. Journal of Vascular Surgery 2006 44, 633-641DOI: (10.1016/j.jvs.2006.04.044) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 6 Leukocyte infiltration into a grafted vein 7 days after operation. CD45-immunostained sections of grafts treated with midkine (MK) short interfering RNA (siRNA) (left) and scrambled siRNA (SCR siRNA) (right) are shown. The bar graph shows the numbers of CD45+ cells in the graft walls (n = 5, *P < 0.05). Bars, 100 μm. Journal of Vascular Surgery 2006 44, 633-641DOI: (10.1016/j.jvs.2006.04.044) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions