Leoligin, the major lignan from Edelweiss, inhibits intimal hyperplasia of venous bypass grafts.
OBJECTIVE
Despite the lower patency of venous compared with arterial coronary artery bypass grafts, approximately 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 [(2S,3R,4R)-4-(3,4-dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)tetrahydrofuran-3-yl]methyl (2Z)-2-methylbut-2-enoat, the major lignan from Edelweiss (Leontopodium alpinum Cass.).


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. 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.
Reisinger
Ute
U
Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innrain 66, A-6020 Innsbruck, Austria.
Schwaiger
Stefan
S
Zeller
Iris
I
Messner
Barbara
B
Stigler
Robert
R
Wiedemann
Dominik
D
Mayr
Tobias
T
Seger
Christoph
C
Schachner
Thomas
T
Dirsch
Verena M
VM
Vollmar
Angelika M
AM
Bonatti
Johannes O
JO
Stuppner
Hermann
H
Laufer
Günther
G
Bernhard
David
D
D000818:Animals; D019659:Asteraceae / Q000737:chemistry*; D001792:Blood Platelets / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D006801:Humans; D006965:Hyperplasia / Q000517:prevention & control; D066298:In Vitro Techniques; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D012501:Saphenous Vein / Q000187:drug effects* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D017705:Lignans; D010936:Plant Extracts; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C542788:leoligin; D050760:Cyclin-Dependent Kinase Inhibitor p27