title: Rapamycin effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties.
abstract: 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.
authors.affiliation: Deutsches Herzzentrum, München, Germany. zohlnhoefer@dhm.mhn.de
authors.forename: Dietlind
authors.initials: D
authors.lastname: Zohlnhöfer
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Nührenberg
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Neumann
authors.forename: Thomas
authors.initials: T
authors.lastname: Richter
authors.forename: Andreas E
authors.initials: AE
authors.lastname: May
authors.forename: Roland
authors.initials: R
authors.lastname: Schmidt
authors.forename: Katja
authors.initials: K
authors.lastname: Denker
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Clauss
authors.forename: Albert
authors.initials: A
authors.lastname: Schömig
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009363:Neoplasm Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007166:Immunosuppressive Agents; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus