Neointima formation, the leading cause of restenosis, is caused by proliferation of coronary artery smooth muscle cells (CASMCs) and is associated with infiltration by monocytes.
Rapamycin inhibits
neointima formation after
stent implantation in humans. It reduces proliferation by its effects on
mammalian target of rapamycin (mTOR)
kinase. In this study, we investigated the expression of mTOR in human
neointima and the effect of
rapamycin on global transcriptional events controlling CASMC phenotype. In neointimal CASMCs, mTOR exhibited increased phosphorylation and was translocated to the nucleus compared with control. Comparative gene expression analysis of CASMCs treated with
rapamycin (100 ng/ml) revealed down-regulation of the
transcription factor E2F-1, a key regulator of G(1)/S-phase entry, and of various
retinoblastoma protein/E2F-1-regulated genes. In addition, we found changes in the expression of genes associated with replication, apoptosis, and extracellular matrix formation. Furthermore,
rapamycin decreased the gene expression of
endothelial monocyte-activating polypeptide-II (
EMAP-II). This decrease of
EMAP-II expression was reflected in a reduced adhesiveness of CASMCs for monocytic cells. Addition of
EMAP-II counteracted the antiadhesive effect of
rapamycin. Therefore,
EMAP-II may comprise a mechanism of
rapamycin-mediated reduction of the proinflammatory activation of CASMCs. The effects reported here of
rapamycin on the down-regulation of genes involved in cell cycle progression, apoptosis, proliferation, and extracellular matrix formation in CASMCs provide an explanation of how
rapamycin reduces CASMC proliferation. In addition,
rapamycin may contribute to a reduction of inflammatory responses by reducing the adhesiveness of CASMC, a mechanism suggested to be mediated by the production and release of
EMAP II.