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Growth-arrest homeobox gene Gax: a molecular strategy to prevent arterial restenosis
1Division of Cardiovascular Research, St. Elizabeth's Medical Center, Boston, MA, USA.
Abstract:
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.
Insights
The Gax (growth arrest homeobox) gene inhibits vascular smooth muscle cell proliferation. Overexpressing Gax may prevent neointima formation in vascular disorders like atherosclerosis and restenosis.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Gene Regulation
Background:
- Vascular remodeling and cellular differentiation changes occur in atherosclerosis and restenosis.
- Nuclear proteins regulating these processes are largely unknown.
- Homeobox genes, like Gax (growth arrest homeobox), are transcription factors involved in cell growth and differentiation.
Purpose of the Study:
- To investigate the role of the Gax gene in vascular smooth muscle cell proliferation and neointima formation.
- To determine if Gax can prevent vascular disorders characterized by neointimal hyperplasia.
Main Methods:
- Studied Gax gene expression in quiescent and mitogen-stimulated vascular smooth muscle cells.
- Assessed the effect of Gax protein microinjection on cell proliferation.
- Utilized replication-defective adenovirus vectors for Gax gene overexpression in cultured cells and in vivo rat carotid artery models.
- Initiated percutaneous Gax adenovirus-mediated gene transfer in rabbit iliac arteries.
Main Results:
- Gax expression is down-regulated in proliferating vascular smooth muscle cells and following balloon angioplasty.
- Microinjection of recombinant Gax protein inhibited mitogen-induced proliferation of cultured vascular smooth muscle cells.
- Overexpression of Gax via adenovirus vector reduced neointima formation and luminal narrowing in rat carotid arteries.
Conclusions:
- Gax gene expression is linked to the non-proliferative phenotype of vascular smooth muscle cells.
- Gax overexpression demonstrates potential as a therapeutic strategy to prevent neointimal formation in vascular disorders.