PMID- 15044617
OWN - NLM
STAT- MEDLINE
DCOM- 20040421
LR  - 20211203
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 65
IP  - 4
DP  - 2004 Apr
TI  - Rapamycin effects transcriptional programs in smooth muscle cells controlling 
      proliferative and inflammatory properties.
PG  - 880-9
AB  - 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.
FAU - Zohlnhofer, Dietlind
AU  - Zohlnhofer D
AD  - Deutsches Herzzentrum, Munchen, Germany. zohlnhoefer@dhm.mhn.de
FAU - Nuhrenberg, Thomas G
AU  - Nuhrenberg TG
FAU - Neumann, Franz-Josef
AU  - Neumann FJ
FAU - Richter, Thomas
AU  - Richter T
FAU - May, Andreas E
AU  - May AE
FAU - Schmidt, Roland
AU  - Schmidt R
FAU - Denker, Katja
AU  - Denker K
FAU - Clauss, Matthias A
AU  - Clauss MA
FAU - Schomig, Albert
AU  - Schomig A
FAU - Baeuerle, Patrick A
AU  - Baeuerle PA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Cytokines)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (small inducible cytokine subfamily E, member 1)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Anti-Inflammatory Agents/pharmacology
MH  - Apoptosis
MH  - Cell Adhesion/drug effects
MH  - Cell Cycle/drug effects
MH  - Cell Division/drug effects
MH  - Cells, Cultured
MH  - Cytokines/metabolism
MH  - Gene Expression/drug effects
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology
MH  - Monocytes/drug effects/physiology
MH  - Muscle, Smooth, Vascular/*drug effects/physiology
MH  - Neoplasm Proteins/metabolism
MH  - Protein Kinases/genetics/*metabolism
MH  - RNA-Binding Proteins/metabolism
MH  - Sirolimus/*pharmacology
MH  - T-Lymphocytes/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Transcription, Genetic/*drug effects
EDAT- 2004/03/27 05:00
MHDA- 2004/04/22 05:00
CRDT- 2004/03/27 05:00
PHST- 2004/03/27 05:00 [pubmed]
PHST- 2004/04/22 05:00 [medline]
PHST- 2004/03/27 05:00 [entrez]
AID - 65/4/880 [pii]
AID - 10.1124/mol.65.4.880 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2004 Apr;65(4):880-9. doi: 10.1124/mol.65.4.880.