Tacrolimus-eluting stent inhibits neointimal hyperplasia via calcineurin/NFAT signaling in porcine coronary artery model.
OBJECTIVE
The purpose is to elucidate the mechanism by which a newly developed tacrolimus-eluting stent (TES) prevents neointimal hyperplasia after stenting.


RESULTS
The three major coronary arteries in juvenile swine were randomized to implantation of either a TES or bare metal stent (BMS). Twelve weeks after stenting, the TES showed 29% less neointimal area than the BMS. Immunohistochemical staining showed that the expression of calcineurin was up-regulated in the neointima and media after stenting, and the TES inhibited this up-regulation. Western blotting demonstrated that the expression of calcineurin, nuclear factor of activated T cell (NFAT), and interleukin-2 (IL-2) was lower with the TES than with the BMS. To confirm the effect of tacrolimus on vascular smooth muscle cells (VSMCs) and its mechanism, cultured rat VSMCs were incubated with 12.5 microM of tacrolimus (tacrolimus group) or without tacrolimus (control group). The cell number of the tacrolimus group was significantly lower than that of the control group at 48 h of incubation. Western blotting demonstrated that tacrolimus decreased the expression of calcineurin, NFATc4, and IL-2 of cultured VSMCs. We confirmed that calcineurin small-interfering RNA (siRNA) decreased cell proliferation and the expression of NFATc4 and IL-2 in cultured VSMCs compared with negative control-siRNA.


CONCLUSIONS
The newly developed TES inhibited neointimal hyperplasia after stenting via the calcineurin/NFAT/IL-2 signaling pathway, which is one of several mechanisms through which TES inhibits restenosis. Calcineurin may be an important molecular target to prevent restenosis after stenting.
Hamada
Narisato
N
Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan.
Miyata
Masaaki
M
Eto
Hideyuki
H
Shirasawa
Takahiro
T
Akasaki
Yuichi
Y
Nagaki
Aya
A
Tei
Chuwa
C
D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000473:pathology*; D054855:Drug-Eluting Stents; D006965:Hyperplasia / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D050778:NFATC Transcription Factors / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D013552:Swine; D016559:Tacrolimus / Q000627:therapeutic use*; D017539:Tunica Intima / Q000473:pathology*
D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D019703:Calcineurin; D016559:Tacrolimus