Gliotoxin inhibits neointimal hyperplasia after vascular injury in rats.

Neointima formation participates in the pathophysiology of atherosclerosis and restenosis. Proliferation and migration of vascular smooth muscle cells (VSMC) are initial responses to vascular injury. The aim of the present study was to assess the effect of gliotoxin, an inhibitor of nuclear factor (NF)-kappaB, on migration and proliferation of cultured rat VSMC and neointimal formation in injured rat vessels. In cultured VSMC, gliotoxin inhibited the nuclear translocation of the p65 subunit of NF-kappaB in response to inflammatory stimuli. In addition, gliotoxin inhibited VSMC migration and proliferation in response to platelet-derived growth factor-BB. This was associated with a rapid rearrangement of the F-actin and vimentin cytoskeleton. Furthermore, gliotoxin inhibited endothelial cell nuclear translocation of p65, cell surface expression of adhesion molecules such as VCAM-1, ICAM-1 and E-selectin, and monocytic cell adhesion to a cytokine-activated endothelial monolayer. In the rat carotid artery balloon catheter injury model, the systemic administration of gliotoxin for 10 days decreased neointimal hyperplasia and luminal stenosis by up to 90% and decreased the expression of proliferating cell nuclear antigen in the vessel wall by up to 70%, depending on the dose. These observations suggest that gliotoxin favorably regulates the response to vascular injury through actions on VSMC. However, further studies evaluating the therapeutic benefit of gliotoxin in restenosis after balloon angioplasty are required.