N-acetylcysteine prevents neointima formation in experimental venous bypass grafts.

Abstract

Neointima formation, mainly characterized by smooth muscle cell proliferation, is an important cause of venous bypass graft failure. The therapeutic potential of the antioxidant N-acetylcysteine (NAC) to attenuate smooth muscle cell proliferation and neointima formation was examined in vivo. The effects of NAC on hyperoxia-induced venous smooth muscle cell (VSMC) cytokine production and proliferation were addressed in vitro. Rats underwent autologous epigastric vein-to-femoral artery interposition grafting. Fourteen rats received oral NAC, and a similar control group received saline. Histomorphometric analysis was performed after 7 days or 3 weeks. Cytokine analysis and cell proliferation assay were performed in cultured human VSMCs after hyperoxic or normoxic exposure and NAC administration. NAC-treated rats displayed a threefold reduction in neointimal area, a sixfold reduction in stenosis rate, and a twofold reduction in VSMC proliferation after vein graft surgery. Incubation of VSMCs in 70 per cent oxygen stimulated the release of mitogenic inflammatory cytokines interleukin (IL) 6 and IL-8. Cytokine-rich medium from these VSMCs induced proliferation of normoxic VSMCs. NAC inhibited hyperoxia-induced cytokine release and VSMC proliferation. NAC attenuated neointima formation and vein graft stenosis by reducing VSMC proliferation in vivo, and prevented hyperoxia-induced cytokine production and VSMC proliferation in vitro.