Antisense to transforming growth factor-beta(1) facilitates the apoptosis of macrophages in rat vein grafts.
BACKGROUND: The success of peripheral vein grafts is limited by intimal hyperplasia. Transforming growth factor (TGF)-beta(1) has effects on cell proliferation, apoptosis and extracellular matrix synthesis. We have previously observed positive changes in vessel healing with antisense to TGF-beta(1). METHODS: Adenovirus was used to transduce rat femoral artery vein grafts with antisense to TGF-beta(1) (Ad-AST) or the sequence encoding the bioactive form of TGF-beta(1) (Ad-BAT). Grafts were harvested at 1, 2, 4 and 12 weeks and formalin fixed for immunohistochemical studies of the cell markers proliferating cellular nuclear antigen (proliferation) and active caspase 3 (apoptosis). In situ DNA fragmentation assays were also performed to confirm active caspase 3 results. RESULTS: Ad-AST treatment significantly (p = 0.05) increased apoptosis of macrophages inside the internal elastic lamina. In addition, Ad-AST treatment significantly increased the cellularity of the graft at early time points and reduced it at later time points (p = 0.01). CONCLUSION: The low levels of TGF-beta(1) in Ad-AST treatment promote apoptosis of macrophages and provide an environment that is more conducive to the proliferation or infiltration of cells that contribute to healthy vessels.
Heaton, NS; Wolff, RA; Malinowski, RL; Hullett, DA; Hoch, JR
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