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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 19, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp059
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.
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Leoligin - the Major Lignan from Edelweiss - Inhibits Intimal Hyperplasia of Venous Bypass Grafts

Ute Reisinger*,1, Stefan Schwaiger*,2, Iris Zeller*,1, Barbara Messner1, Robert Stigler1, Dominik Wiedemann1, Tobias Mayr1, Christoph Seger3, Thomas Schachner1, Verena M. Dirsch4, Angelika M. Vollmar5, Johannes O. Bonatti1, Hermann Stuppner2, Günther Laufer1 and David Bernhard1

1 Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innrain 66, A-6020 Innsbruck, Austria
2 Institute of Pharmacy / Pharmacognosy, University of Innsbruck, Josef-Moeller-Haus, Innrain 52c, A-6020 Innsbruck, Austria
3 Central Institute for Medical and Chemical Laboratory Diagnostics, Innsbruck Medical University, Innsbruck, Austria
4 Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria
5 Department of Pharmacy, Center of Drug Research, University of Munich, 81377 Munich, Germany

Correspondence: David Bernhard Ph.D., Head of the Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innrain 66, 6020 Innsbruck, Austria. Tel.: 0043-512-504-27815; FAX: 0043-512-504-27805; e-mail: David.Bernhard{at}i-med.ac.at.

Aims: Despite the lower patency of venous compared to arterial coronary artery bypass grafts, about 50% of grafts used are saphenous vein conduits because of their easier accessibility. In a search for ways to increase venous graft patency, we applied the results of a previous pharmacological study screening for non-toxic compounds that inhibit intimal hyperplasia of saphenous vein conduits in organ cultures. Here we analyse the effects and mechanism of action of leoligin, the major lignan [(2S,3R,4R)-4-(3,4-dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)tetrahydrofuran-3-yl]methyl (2Z)-2-methylbut-2-enoat from Edelweiss (Leontopodium alpinum Cass.).

Methods and Results: We found that leoligin potently inhibits vascular smooth muscle cell (SMC) proliferation by inducing cell cycle arrest in the G1-phase. Leoligin induced cell death neither in SMCs, nor, more importantly, in endothelial cells (ECs). In a human saphenous vein organ culture model for graft disease, leoligin potently inhibited intimal hyperplasia, and even reversed graft disease in pre-damaged vessels. Furthermore, in an in vivo mouse model for venous bypass graft disease, leoligin potently inhibited intimal hyperplasia.

Conclusions: Our data suggest that leoligin might represent a novel non-toxic, non-thrombogenic, endothelial integrity preserving candidate drug for the treatment of vein graft disease.

KEYWORDS lignan; neointima; therapy; intimal hyperplasia

Time for primary review: 32 Days

* These authors contributed equally to this work.


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