INHIBITION OF COLLAGEN-SYNTHESIS, SMOOTH-MUSCLE CELL-PROLIFERATION, AND INJURY-INDUCED INTIMAL HYPERPLASIA BY HALOFUGINONE

Proliferation of vascular smooth muscle cells (SMCs) and accumulation of extracellular matrix (ECM) components within the arterial wall in r esponse to local injury are important etiologic factors in vascular pr oliferative disorders such as arteriosclerosis and restenosis after an gioplasty. Fibrillar and nonfibrillar collagens are major constituents of the ECM that modulate cell shape and proliferative responses and t hereby contribute to the pathogenesis of intimal hyperplasia. Halofugi none, an anticoccidial quinoazolinone derivative, inhibits collagen ty pe I gene expression. We investigated the effect of halofuginone on (1 ) proliferation of bovine aortic endothelial cells and SMCs derived fr om the same specimen and maintained in vitro, (3) ECM deposition and c ollagen type I synthesis and gene expression, and (3) injury-induced i ntimal hyperplasia in vivo. DNA synthesis and proliferation of vascula r SMCs in response to serum or basic fibroblast growth factor were abr ogated in the presence of as little as 0.1 mu g/mL halofuginone; this inhibition was reversible upon removal of the compound. Under the same conditions, halofuginone exerted a relatively small antiproliferative effect on the respective vascular endothelial cells. Halofuginone als o inhibited the synthesis and deposition of ECM components by vascular SMCs as indicated both by a substantial reduction in the amount of su lfated proteoglycans and collagen type I synthesis and gene expression . Local administration of halofuginone in the rabbit ear model of crus h injury-induced arterial intimal hyperplasia resulted in a 50% reduct ion in intimal thickening as measured by a morphometric analysis of th e neointima/media ratio. The differential inhibitory effect of halofug inone on vascular SMCs versus endothelial cells, its inhibition of ECM deposition and collagen type I synthesis, and its ability to attenuat e injury-induced intimal hyperplasia may place halofuginone alone or i n combination with other antiproliferative compounds as a potential ca ndidate for prevention of arterial stenosis and accelerated atheroscle rosis.