Transforming growth factor-beta1 antisense treatment of rat vein grafts reduces the accumulation of collagen and increases the accumulation of h-caldesmon.
BACKGROUND: The main cause of occlusion and vein graft failure after peripheral and coronary arterial reconstruction is intimal hyperplasia. Transforming growth factor beta-1 (TGF-beta1) is a pleiotropic cytokine known to have powerful effects on cell growth, apoptosis, cell differentiation, and extracellular matrix synthesis. METHODS: To investigate the role of TGF-beta1 in intimal hyperplasia, we used adenovirus to deliver to superficial epigastric vein messenger RNA (mRNA) antisense to TGF-beta1 (Ad-AST) or the sequence encoding the bioactive form of TGF-beta1 (Ad-BAT). Infection with "empty" virus was used as a control (Ad-CMVpLpA). The treated vein was then used for an interposition graft into rat femoral artery. Grafts were harvested at 1, 2, 4, and 12 weeks and formalin-fixed for histologic studies or placed in liquid nitrogen for mRNA studies. RESULTS: Ad-AST treatment resulted in an overall reduction of TGF-beta1 expression (P = .001), and Ad-BAT treatment resulted in an overall increase in TGF-beta1 expression (P = .007). Histologic analysis showed Ad-AST caused reduced collagen build up in the neointima at 12 weeks (P = .0001). Immunohistochemical staining for h-caldesmon at 12 weeks indicated Ad-AST increased smooth muscle cells throughout the vessel wall compared with Ad-CMVpLpA (P = .0024) or Ad-BAT (P = .04). Ad-AST also resulted in reduced CD68-positive cells in the media/adventitia (P = .005 vs Ad-CMVpLpA, P = .01 vs Ad-BAT). To further understand how Ad-AST was influencing the build up of collagen, we performed quantitative polymerase chain reaction on complimentary DNA (cDNA) from homogenates of the vein grafts. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) was increased at 1 week by Ad-BAT (P = .048 vs Ad-CMVpLpA) and decreased by Ad-AST at all time points (P
Wolff, RA; Malinowski, RL; Heaton, NS; Hullett, DA; Hoch, JR
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