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Molecular Pharmacology

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Research ArticleArticle

Rapamycin Effects Transcriptional Programs in Smooth Muscle Cells Controlling Proliferative and Inflammatory Properties

Dietlind Zohlnhöfer, Thomas G. Nührenberg, Franz-Josef Neumann, Thomas Richter, Andreas E. May, Roland Schmidt, Katja Denker, Matthias A. Clauss, Albert Schömig and Patrick A. Baeuerle
Molecular Pharmacology April 2004, 65 (4) 880-889; DOI: https://doi.org/10.1124/mol.65.4.880
Dietlind Zohlnhöfer
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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Thomas G. Nührenberg
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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Franz-Josef Neumann
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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Thomas Richter
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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Andreas E. May
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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Roland Schmidt
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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Katja Denker
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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Matthias A. Clauss
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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Albert Schömig
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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Patrick A. Baeuerle
Deutsches Herzzentrum (D.Z., T.G.N., A.E.M., R.S., K.D., A.S.) and Institut für Pathologie (T.R.), Technische Universität München, Munich, Germany; Micromet AG, Munich, Germany (P.A.B.); Herz-Zentrum, Bad Krozingen, Germany (F.-J.N.); and Indiana Center for Vascular Biology & Medicine, Indianapolis, Indiana (M.A.C.)
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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 G1/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.

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Molecular Pharmacology: 65 (4)
Molecular Pharmacology
Vol. 65, Issue 4
1 Apr 2004
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Research ArticleArticle

Rapamycin Effects Transcriptional Programs in Smooth Muscle Cells Controlling Proliferative and Inflammatory Properties

Dietlind Zohlnhöfer, Thomas G. Nührenberg, Franz-Josef Neumann, Thomas Richter, Andreas E. May, Roland Schmidt, Katja Denker, Matthias A. Clauss, Albert Schömig and Patrick A. Baeuerle
Molecular Pharmacology April 1, 2004, 65 (4) 880-889; DOI: https://doi.org/10.1124/mol.65.4.880

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Research ArticleArticle

Rapamycin Effects Transcriptional Programs in Smooth Muscle Cells Controlling Proliferative and Inflammatory Properties

Dietlind Zohlnhöfer, Thomas G. Nührenberg, Franz-Josef Neumann, Thomas Richter, Andreas E. May, Roland Schmidt, Katja Denker, Matthias A. Clauss, Albert Schömig and Patrick A. Baeuerle
Molecular Pharmacology April 1, 2004, 65 (4) 880-889; DOI: https://doi.org/10.1124/mol.65.4.880
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