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Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 20, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm076
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EMAP-II downregulation contributes to the beneficial effects of Rapamycin after vascular injury

Thomas G. Nührenberg, MD1,*, Nicolas Langwieser, MD*, Johannes B.K. Schwarz, DVM1, Yonghao Hou, MD2, Pamela Frank, DVM1,5, Falko Sorge1, Susanne Matschurat, PhD3, Stefan Seidl, MD4, Albert Schömig, MD1, Matthias A. Clauss, PhD2 and Dietlind Zohlnhöfer, MD1,

1 I. Medizinische Klinik und Deutsches Herzzentrum der Technischen Universität München, Germany
2 Indiana Center for Vascular Biology & Medicine, Indianapolis, USA
3 formerly Molekulare Zellbiologie, Max-Plank-Institut für Herz- und Lungenforschung, Bad Nauheim, Germany
4 Institut für Pathologie
5 Institut für experimentelle Chirurgie

Address of correspondence: Dietlind Zohlnhöfer, M.D. I. Medizinische Klinik und Deutsches Herzzentrum der Technischen Universität München, Lazarettstr. 36, D-80636 München, Germany Tel.: +49-89-1218-4012, Fax: +49-89-1218-4013, E-mail: d_zohlnhoefer{at}yahoo.com

Aims: Neointima formation after vascular injury is strongly associated with inflammation. Rapamycin inhibits human neointima formation and reduces expression of the proinflammatory cytokine endothelial-monocyte activating peptide II (EMAP-II) in vitro. Here we investigated the interplay between EMAP-II and rapamycin after vascular injury in vivo.

Methods: In a mouse model of vascular injury, mice were either not treated, given everolimus, a rapamycin derivate, or subjected to simultaneous challenge with everolimus and EMAP-II. EMAP-II expression was measured in coronary artery smooth muscle cells (CASMC) and monocytic cells in vitro and in patients after percutaneous coronary intervention (PCI) .

Results: After vascular injury, rapamycin reduced neointima formation and adventitial thickening. Immunohistochemistry revealed reduced EMAP-II protein expression and suppressed recruitment of inflammatory cells. Simultaneous challenge with EMAP-II counteracted these effects of rapamycin. Expression of EMAP-II and its inhibition by rapamycin was confirmed in CASMC and monocytic cells. In patients, EMAP-II upregulation was confined to PCI of distal coronary artery segments and profoundly suppressed by oral rapamycin treatment.

Conclusions: These data suggest important yet unrecognized roles of EMAP-II and adventitial inflammation in neointima formation: Through inhibition of EMAP-II, rapamycin reduces the recruitment of inflammatory cells to the adventitia and supports an early and bland healing.

KEYWORDS restenosis; inflammation; adventitia; endothelium; drugs

Time for primary review: 25

* These authors contributed equally to this work.


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