Ubiquitin, Proteasome, and Restenosis

Abstract

In the present issue of Circulation , Meiners and his colleagues1 show that local application of a proteasome inhibitor resulted in significant inhibition of intimal hyperplasia in a balloon injury model in rat carotid artery. This report is of interest because it identifies a novel target for the treatment of restenosis and introduces a rapidly developing field in basic science to cardiovascular researchers. Proteasomes are large intracellular protein complexes that specialize in degrading cellular proteins that are either unneeded or damaged.2–5⇓⇓⇓ Inhibiting the activity of proteasome not only stops the ability of the cell to get rid of unwanted proteins, but also blocks most cellular processes critical for a cell’s survival. Inhibitors of proteasome activity have been used widely in basic research and more recently in anticancer clinical trials. It is not surprising that proteasome inhibitors can inhibit intimal hyperplasia because they generally have antiproliferative, antiinflammatory, and proapoptotic properties. In order to understand the inner workings of proteasome, one must become acquainted with a small protein called ubiquitin that serves as a molecular tag directing unneeded or damaged proteins to the proteasome for degradation. See p 483 Ubiquitin, a 76 amino acid protein, is highly conserved in evolution with only a 3 amino acid difference between yeast and human homologues. Most of the known function of ubiquitin resides in its ability to covalently attach to other proteins through the formation of an isopeptide bond attaching the C-terminal Glycine residue of ubiquitin to a Lysine residue of the target protein.2,4,5⇓⇓ A second ubiquitin then attaches to the first ubiquitin to build up a polyubiquitin chain, which is required for the tagged protein to be recognized by the proteasome. The process of attaching ubiquitin molecules to other proteins is termed ubiquitination; it occurs through …