Effects of tacrolimus or sirolimus on proliferation of vascular smooth muscle and endothelial cells.
Local strategies directed against vascular smooth muscle cell (VSMC) proliferation such as drug-eluting stents reduce the occurrence of restenosis. However, these approaches may also inhibit endothelial cell (EC) proliferation and, thus, impair reendothelialization. We compared the effects of tacrolimus on human VSMC and EC proliferation and migration to sirolimus, a compound with similar molecular structure. Thymidine incorporation was determined in growth factor-stimulated VSMC and EC. The drug concentration at which maximal VSMC proliferation was inhibited by 50% (IC50) was about 10-fold higher for tacrolimus (3.8 x 10 M) than for sirolimus (4.1 x 10 M; P = 0.055). It is interesting that the molar IC50 value in EC was around 10-fold higher for tacrolimus (2.3 x 10 M) than for sirolimus (7.1 x 10 M; P < 0.01). The profile of these drugs on VSMC and EC migration was similar to the one found in the proliferation assays. Inhibition of VSMC proliferation by both tacrolimus and sirolimus was associated with upregulation of the cell-cycle inhibitor p27. Thus, tacrolimus is less potent than sirolimus for inhibiting VSMC proliferation or migration. However, tacrolimus exerts markedly less antiproliferative effects on EC compared with sirolimus. In combination with its potent antiinflammatory effects, tacrolimus may represent a promising compound for the use in drug-eluting stents.
Matter
Christian M
CM
Cardiovascular Research, Institute of Physiology, Zurich University and CardioVascular Center, University Hospital Zurich, Switzerland. cmatter@physiol.unizh.ch
Rozenberg
Izabela
I
Jaschko
Andrea
A
Greutert
Helen
H
Kurz
David J
DJ
Wnendt
Stephan
S
Kuttler
Bernd
B
Joch
Hana
H
Grünenfelder
Jürg
J
Zünd
Gregor
G
Tanner
Felix C
FC
Lüscher
Thomas F
TF
D015153:Blotting, Western; D002452:Cell Count / Q000379:methods; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D018797:Cell Cycle Proteins; D007166:Immunosuppressive Agents; D010982:Platelet-Derived Growth Factor; D014316:Tritium; D004247:DNA; D013936:Thymidine; D020123:Sirolimus; D016559:Tacrolimus