The aforementioned studies demonstrated that inhibition of protein geranylgerany-lation results in VSMC growth inhibition and apoptosis. Inhibition of protein farnesylation also inhibited VSMC proliferation, although to a lesser degree, but did not induce apoptosis. We next evaluatedwhetherthis VSMC growth inhibition by prenyltransferase inhibitors could also occur in vivo. To this end, we determined the ability of GGTI-297 and FTI-276 to inhibit neointimal hyperplasia in vivo in a rat carotid artery injury model. Vascular injury was created by introducing a balloon catheter via external carotid artery. Two weeks after injury, the vehicle-treated animals had pronounced neointimal hyperplasia. In contrast, rats treatedwith GGTI-297 (12.5 mg/kg/d) delivered from a 7-dmini-pump through a catheter cannulated to the contralateral jugular vein at the time ofcarotid angioplasty, had reduced neointimal formation (85). The intimal thickness from injured animals treated with DMSO vehicle was 32.8 ± 4.1 ^m. GGTI-297 treatment had a pronounced effect on the development of neointimal hyperplasia reducing the neointimal thickening by 72% of that observed in the vehicle only treated groups (85).
We next investigated the ability of the FTase inhibitor FTI-276 to inhibit neointimal formation in the same rat carotid artery injury model. In contrast to GGTI-297, the effects ofFTI-276 on VSMC proliferation after angioplasty is not as pronounced. FTI-276 treatment resulted in only a 44% reduction in neointimal thickening (85).
Was this article helpful?