title: Differential effect of atorvastatin and tacrolimus on proliferation of vascular smooth muscle and endothelial cells.
abstract: Although considered promising for use in drug-eluting stents (DES), tacrolimus failed clinically. Tacrolimus inhibits growth factor production but can also act as a growth factor on vascular smooth muscle cells (VSMC). This unexpected proliferative stimulus could reverse the beneficial effects of the drug on restenosis. We hypothesized that tacrolimus' association with statins, which lower cholesterol and impair cell proliferation, could restore tacrolimus' beneficial effect by abrogating the aberrant proliferative stimulus. Additionally, since maintenance of endothelial function represents a challenge for new-generation DES, we investigated the combined effect of tacrolimus and atorvastatin on endothelial cells. Human VSMC and umbilical vein endothelial cells (HUVEC) were incubated with 100 nM tacrolimus and increasing doses of atorvastatin (0-3.0 μM). Atorvastatin plus tacrolimus dose-dependently inhibited VSMC proliferation. The percentage of cells incorporating 5-bromo-2'-deoxyuridine (BrdU) in their DNA was 49 ± 14% under basal conditions, 62 ± 15% (P = 0.01) with tacrolimus, 40 ± 22% with 3 μM atorvastatin, and 30 ± 7% (P < 0.05) with 3 μM atorvastatin plus tacrolimus. Atorvastatin downregulated β-catenin, Erk1 and Erk2, and cyclin B in tacrolimus-stimulated VSMC. In contrast, atorvastatin plus tacrolimus did not affect proliferation of endothelial cells. The percentage of HUVEC incorporating BrdU in their DNA was 47 ± 8% under basal conditions, 58 ± 6% (P = 0.01) with tacrolimus, 45 ± 4% with 3 μM atorvastatin, and 49 ± 1% with 3 μM atorvastatin plus tacrolimus. Both agents stimulated endoglin production by HUVEC. Taken together, these results suggest that, when combined with tacrolimus, atorvastatin exerts a dose-dependent antiproliferative effect on VSMC. In contrast, atorvastatin acts in concert with tacrolimus in HUVEC to stimulate production of endoglin, a factor that has an important role in endothelial repair. Our study supports the conclusion that prevention of postcoronary in-stent restenosis and late thrombosis may benefit of concomitant association of tacrolimus and high doses of atorvastatin.
authors: Invasive Cardiology Unit, Pineta Grande Hospital, Castelvolturno, Italy.
authors: Arturo
authors: A
authors: Giordano
authors: Simona
authors: S
authors: Romano
authors: Mario
authors: M
authors: Monaco
authors: Antonio
authors: A
authors: Sorrentino
authors: Nicola
authors: N
authors: Corcione
authors: Anna Laura
authors: AL
authors: Di Pace
authors: Paolo
authors: P
authors: Ferraro
authors: Giovanna
authors: G
authors: Nappo
authors: Michele
authors: M
authors: Polimeno
authors: Maria Fiammetta
authors: MF
authors: Romano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D000069059:Atorvastatin; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019926:Cyclin B / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D054855:Drug-Eluting Stents; D000071063:Endoglin; D006538:Heptanoic Acids / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D016559:Tacrolimus / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C495270:CTNNB1 protein, human; D002317:Cardiovascular Agents; D019926:Cyclin B; C064206:ENG protein, human; D000071063:Endoglin; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D011956:Receptors, Cell Surface; D051176:beta Catenin; D000069059:Atorvastatin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016559:Tacrolimus