Growth-arrest homeobox gene Gax: a molecular strategy to prevent arterial restenosis.

Tissue remodeling and alterations in cellular differentiation occur during atherosclerosis and restenosis following balloon angioplasty, but little is known about the nuclear proteins that regulates these processes. Homeobox genes encode transcription factors that regulate cell growth, differentiation, migration, and body plan formation. The Gax (growth arrest homeobox) gene is expressed in adult cardiovascular tissues. Gax is expressed in normal quiescent smooth muscle cells, but its expression is rapidly down-regulated when these cells are stimulated to proliferate with mitogens. Gax expression is also down-regulated in vascular tissue immediately following balloon injury. These characteristics of Gax suggest it may be required to maintain the non-proliferative or contractile phenotype in vascular smooth muscle. Indeed, the mitogen-induced proliferation of cultured vascular smooth muscle cells is inhibited when these cells are microinjected with recombinant Gax protein. Gax also inhibits the proliferation of vascular smooth muscle cells when overexpressed with a replication-defective adenovirus vector, and the local delivery of this recombinant virus to denuded rat carotid arteries significantly reduces neointima formation and luminal narrowing. Currently we are performing percutaneous Gax adenovirus-mediated gene transfer into normal and atherosclerotic rabbit iliac arteries. These data suggest that overexpression of Gax gene may prevent the neointimal formation that is characteristic of a number of vascular disorders.