SUMMARY OF WORK Significant improvements in the primary success rate of various medical and surgical treatments of atherosclerotic disease have been made in the last few years. Yet recurring failures continue in 30 to 50% of the patients after balloon angioplasty, bypass surgery, and endarterectomy because of late restenosis of the treated vessel. The restenosis is a result of a complex series of fibroproliferative responses to the vascular injury that results in vascular smooth muscle cell (VSMC) proliferation, migration, neointimal accumulation, and secretion of extracellular proteins. Microtubules are likely involved in controlling or moderating critical intracellular mechanisms necessary for the VSMC fibroproliferative response. We hypothesize that stabilizing microtubules with paclitaxel or other agents may disrupt the mechanisms involved in the fibroproliferative response of the smooth muscle cells and therefore limit the cellular response to injury. We previously found that both paclitaxel and D2O, microtubule stabilizing agents, inhibited VSMC proliferation, migration, and invasion in vitro and prevented neointimal VSMC accumulation in the rat carotid artery after balloon dilation and endothelial denudation injury. The paclitaxel concentrations necessary for inhibiting neointimal formation were 100 to 1000 times lower than the levels measured for the treatment of tumors in comparable assays. Atherosclerosis is a chronic form of vascular injury involving both an inflammatory response and a change in the normal vascular smooth muscle cells similar to the more acute changes found in the angioplasty/restenosis model. Since paclitaxel and D2O were effective in reducing neointimal formation in our initial studies, we have begun studies testing the efficacy of D2O (25% drinking water) and paclitaxel (2 mg/ kg b.w. per week) to limit the development and progression of atherosclerosis using the animal model, apoE knockout mice. The treatment periods were 6 and 16 weeks. Similar atherosclerotic lesions were seen in the aortic arch regardless of the treatment. We conclude that chronic systemic treatment with microtubule stabilizing agents was not effective in altering the course of atherosclerosis in the ApoE mouse.
NIH ExPorter
NIH ExPorter