Fluvastatin accelerates re-endothelialization impaired by local sirolimus treatment.
Sirolimus-eluting stent reduces restenosis after percutaneous coronary intervention. However, accumulating evidence suggests that sirolimus potentially affects re-endothelialization, leading to late thrombosis. Statins have protective effects on endothelium. Recently, statins are reported to increase the number of circulating endothelial progenitor cells (EPCs) and accelerate re-endothelialization after vascular injury. Here, we tested the hypothesis that fluvastatin has beneficial effect on re-endothelialization after local sirolimus treatment. We performed wire-mediated vascular injury to both sides of femoral arteries of wild-type mice and bone marrow chimeric mice. Either sirolimus (100 microg) or DMSO was administered locally to the perivascular area of the injured arteries. All mice received either fluvastatin (5 mg/kg/day) or vehicle by gavage starting at one week before the surgery until sacrifice. At 4 weeks after the surgery, re-endothelialization of the sirolimus-treated artery was significantly less than that of DMSO-treated one in the vehicle-treated mice as determined by the percentage of CD31-positive area (P<0.05). Systemic administration of fluvastatin accelerated the re-endothelialization in the sirolimus-treated artery to the similar degree of that in the DMSO-treated artery (P=NS). Contribution of bone marrow-derived cells to re-endothelialization was seldom observed in bone marrow chimeric mice regardless of fluvastatin administration. Fluvastatin significantly ameliorated proliferation (2.5-folds) and migration activities (2.3-folds) of mature endothelial cells impaired by sirolimus treatment (P<0.05, respectively). Fluvastatin increased endothelial nitric oxide synthase expression and decreased plasminogen activator inhibitor-1 expression in mature endothelial cell in the presence of sirolimus (P<0.05, respectively). Our findings suggest that fluvastatin has protective effects against impaired re-endothelialization after sirolimus treatment.
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
Daiju
D
Fukuda
Soichiro
S
Enomoto
Ibuki
I
Shirakawa
Ryozo
R
Nagai
Masataka
M
Sata
D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D005263:Femoral Artery / Q000293:injuries; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D000077340:Fluvastatin; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011897:Random Allocation; D020123:Sirolimus / Q000494:pharmacology*; D013997:Time Factors; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism; D017540:Tunica Media / Q000166:cytology / Q000378:metabolism
D005229:Fatty Acids, Monounsaturated; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D007211:Indoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000077340:Fluvastatin; D016650:Fluorescein-5-isothiocyanate; D020123:Sirolimus