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 Clauss, Albert Schömig, Patrick A. Baeuerle

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)880-889
Number of pages10
JournalMolecular Pharmacology
Volume65
Issue number4
DOIs
StatePublished - Apr 2004

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Sirolimus
Smooth Muscle Myocytes
Coronary Vessels
Neointima
Adhesiveness
Gene Expression
Extracellular Matrix
Down-Regulation
E2F1 Transcription Factor
Apoptosis
Retinoblastoma Protein
G1 Phase
S Phase
Genes
Stents
Monocytes
Cell Cycle
Phosphotransferases
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Pharmacology

Cite this

Zohlnhöfer, D., Nührenberg, T. G., Neumann, F. J., Richter, T., May, A. E., Schmidt, R., ... Baeuerle, P. A. (2004). Rapamycin Effects Transcriptional Programs in Smooth Muscle Cells Controlling Proliferative and Inflammatory Properties. Molecular Pharmacology, 65(4), 880-889. https://doi.org/10.1124/mol.65.4.880

Rapamycin Effects Transcriptional Programs in Smooth Muscle Cells Controlling Proliferative and Inflammatory Properties. / Zohlnhöfer, Dietlind; Nührenberg, Thomas G.; Neumann, Franz Josef; Richter, Thomas; May, Andreas E.; Schmidt, Roland; Denker, Katja; Clauss, Matthias; Schömig, Albert; Baeuerle, Patrick A.

In: Molecular Pharmacology, Vol. 65, No. 4, 04.2004, p. 880-889.

Research output: Contribution to journalArticle

Zohlnhöfer, D, Nührenberg, TG, Neumann, FJ, Richter, T, May, AE, Schmidt, R, Denker, K, Clauss, M, Schömig, A & Baeuerle, PA 2004, 'Rapamycin Effects Transcriptional Programs in Smooth Muscle Cells Controlling Proliferative and Inflammatory Properties', Molecular Pharmacology, vol. 65, no. 4, pp. 880-889. https://doi.org/10.1124/mol.65.4.880
Zohlnhöfer, Dietlind ; Nührenberg, Thomas G. ; Neumann, Franz Josef ; Richter, Thomas ; May, Andreas E. ; Schmidt, Roland ; Denker, Katja ; Clauss, Matthias ; Schömig, Albert ; Baeuerle, Patrick A. / Rapamycin Effects Transcriptional Programs in Smooth Muscle Cells Controlling Proliferative and Inflammatory Properties. In: Molecular Pharmacology. 2004 ; Vol. 65, No. 4. pp. 880-889.
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