Differential effect of atorvastatin and tacrolimus on proliferation of vascular smooth muscle and endothelial cells
| Autor: | Arturo Giordano, Nicola Corcione, Paolo Ferraro, Simona Romano, Antonio Sorrentino, Anna Laura Di Pace, Mario Monaco, Michele Polimeno, Maria Fiammetta Romano, Giovanna Nappo |
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| Přispěvatelé: | Giordano, A, Romano, Simona, Monaco, M, Sorrentino, A, Corcione, N, Di Pace, Al, Ferraro, P, Nappo, G, Polimeno, M, Romano, MARIA FIAMMETTA |
| Rok vydání: | 2012 |
| Předmět: |
Male
Time Factors Vascular smooth muscle Physiology medicine.medical_treatment Atorvastatin Pharmacology Muscle Smooth Vascular Myocyte Phosphorylation Receptor Cells Cultured beta Catenin Aged 80 and over Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Endoglin Drug-Eluting Stents surgical procedures operative lipids (amino acids peptides and proteins) Signal transduction Cardiology and Cardiovascular Medicine medicine.drug DNA Replication proliferation Myocytes Smooth Muscle Receptors Cell Surface chemical and pharmacologic phenomena Cyclin B Tacrolimus Antigens CD Physiology (medical) Human Umbilical Vein Endothelial Cells medicine Humans Pyrroles cardiovascular diseases Aged Cell Proliferation Dose-Response Relationship Drug vascular cell business.industry Growth factor statin nutritional and metabolic diseases Cardiovascular Agents Heptanoic Acids Hydroxymethylglutaryl-CoA Reductase Inhibitors business |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 302:H135-H142 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.00490.2011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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