Antisense to transforming growth factor-β1 messenger RNA reduces vein graft intimal hyperplasia and monocyte chemotactic protein 1 Randal A. Wolff, PhD,

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Antisense to transforming growth factor-β1 messenger RNA reduces vein graft intimal hyperplasia and monocyte chemotactic protein 1 Randal A. Wolff, PhD, Masaaki Ryomoto, MD, V. Emily Stark, MS, Rita Malinowski, BS, Jeffrey J. Tomas, BS, Michelle A. Stinauer, BS, Debra A. Hullett, PhD, John R. Hoch, MD Journal of Vascular Surgery Volume 41, Issue 3, Pages 498-508 (March 2005) DOI: 10.1016/j.jvs.2004.12.037 Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 1 Adenovirus gene expression is seen out to 4 weeks. Grafts were treated ex vivo with 1 × 107 plaque forming units per milliliter of adenovirus containing the gene for β-galactosidase before placement. The grafts were then harvested at the indicated time points and soaked in a solution containing χ-Gal before being fixed and examined microscopically. For each time point, n = 5 vein grafts. β-gal, β-Galactosidase. Journal of Vascular Surgery 2005 41, 498-508DOI: (10.1016/j.jvs.2004.12.037) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 2 Expression of antisense to transforming growth factor β1 (tgf-β1) greatly reduces the level of tgf-β1 messenger RNA (mRNA). The grafts were harvested at the indicated time points, rinsed with phosphate-buffered saline, and homogenized; the mRNA was extracted and reverse-transcribed; and measurements were made by quantitative polymerase chain reaction, with normalization to mRNA levels of hypoxanthine phosphoribosyltransferase (hprt). For illustrative purposes, ‡P ≤ .01; however, statistical analysis indicated that the relationships between groups did not change with time. When time is removed as a factor, the reduction of tgf-β1 mRNA by Ad-AST is significant (P < .0001 vs Ad-GAL, sham, or Ad-CMVpLpA). Results from ungrafted epigastric vein are given as time 0. For each treatment/time point, n = 5 vein grafts. Journal of Vascular Surgery 2005 41, 498-508DOI: (10.1016/j.jvs.2004.12.037) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 3 Expression of antisense to transforming growth factor β1 (tgf-β1) greatly reduces the level of TGF-β1 protein. The grafts were harvested at the indicated time points, rinsed with phosphate-buffered saline, and homogenized, and the supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA). Top, Acid activation followed by neutralization allowed measurement of the total TGF-β1 in the sample. Bottom, Without acid activation, the ELISA was specific for bioactive TGF-β1. The reduction in total and bioactive TGF-β1 was significant vs each control at each time point (‡P ≤ .01; *P ≤ .05). Results from ungrafted epigastric vein are given as time 0. For each treatment/time point, n = 5 vein grafts. Journal of Vascular Surgery 2005 41, 498-508DOI: (10.1016/j.jvs.2004.12.037) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 4 Vein graft cross sections show reduced transforming growth factor β1 (TGF-β1) expression. The grafts were harvested at the indicated time points, fixed, and paraffin embedded. Sections were subjected to immunohistochemistry by using a monoclonal antibody specific to TGF-β1. Overall, sham grafts showed the most staining for TGF-β1, and Ad-AST grafts showed the least. ‡P ≤ .01; *P ≤ .05 vs Ad-AST at the same time point. Results from ungrafted epigastric vein are given as time 0. For each treatment/time point, n = 5 vein grafts. Journal of Vascular Surgery 2005 41, 498-508DOI: (10.1016/j.jvs.2004.12.037) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 5 Micrographs of 12-week vein grafts show reduced intimal hyperplasia with Ad-AST. Grafts were transfected before implantation with adenovirus that expressed β-galactosidase (top left), antisense to transforming growth factor β1 (top right), or empty virus (bottom left). Ungrafted epigastric vein is shown at the bottom right. Neointimal growth is dramatically diminished in the antisense-treated graft, with preservation of the adventitial/medial layer. Arrows indicate the internal elastic laminas. L, Lumen; N, neointima; A, adventitia/media. Each picture was taken at ×100 magnification. Journal of Vascular Surgery 2005 41, 498-508DOI: (10.1016/j.jvs.2004.12.037) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 6 Reduction in transforming growth factor β1 (TGF-β1) reduces monocyte chemotactic protein 1 (MCP-1) messenger RNA (mRNA). Overall, the reduction in mcp-1 mRNA in the Ad-AST group was significant vs each of the control groups, but this effect did not reach significance at all time points individually. Because tgf-β1 and mcp-1 mRNA were both measured for each of the grafts, further analysis was able to show that the reduction in mcp-1 mRNA was completely dependent on the reduction in tgf-β1 (P < .0001). Measurements were made by relative quantitative polymerase chain reaction with normalization to mRNA levels of hypoxanthine phosphoribosyltransferase (HPRT). For each treatment/time point, n = 5 vein grafts. Journal of Vascular Surgery 2005 41, 498-508DOI: (10.1016/j.jvs.2004.12.037) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions