ANTISENSE OLIGONUCLEOTIDES TO THE P65 SUBUNIT OF NF-KB INHIBIT HUMAN VASCULAR SMOOTH-MUSCLE CELL ADHERENCE AND PROLIFERATION AND PREVENT NEOINTIMA FORMATION IN RAT CAROTID ARTERIES

Neointima formation associated with vascular restenosis is a complex l ocal inflammatory process actively involving the major cellular compon ent of the atherosclerotic lesion, the vascular smooth muscle cell. NF -kB is a pleotrophic transactivator of a diverse group of genes whose activation has been strongly associated with the cellular response to inflammation. We treated human vascular smooth muscle cells (VSMC) wit h phosphorothio antisense oligonucleotides to the p65 subunit of NF-kB and report that addition of p65 antisense oligonucleotides (1-20 mu M ), but not sense or p50, inhibit human VSMC adherence and proliferatio n in a concentration-dependent manner. Additionally, administration of p65 antisense significantly inhibited neointima formation in balloon angioplasty treated rat carotid arteries, indicating that the p65 subu nit of NF-kB transactivates genes whose expression is important in VSM C pathobiology. These results suggest that abrogation of p65 reduces n eointima formation by inhibition of smooth muscle cell proliferation a nd adherence. (C) 1995 Academic Press, Inc.