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Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells

BACKGROUND: Sirolimus-eluting stents (CYPHER stents) demonstrated remarkable efficacy in reducing restenosis rates in patients with coronary artery disease. There is a concern of sub-acute and late stent thrombosis. Tissue factor (TF) is critical in thrombosis. This study investigated the effect of...

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Autores principales: Zhu, Shengsi, Viswambharan, Hema, Gajanayake, Thusitha, Ming, Xiu-Fen, Yang, Zhihong
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1190166/
https://www.ncbi.nlm.nih.gov/pubmed/16018822
http://dx.doi.org/10.1186/1471-2261-5-22
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author Zhu, Shengsi
Viswambharan, Hema
Gajanayake, Thusitha
Ming, Xiu-Fen
Yang, Zhihong
author_facet Zhu, Shengsi
Viswambharan, Hema
Gajanayake, Thusitha
Ming, Xiu-Fen
Yang, Zhihong
author_sort Zhu, Shengsi
collection PubMed
description BACKGROUND: Sirolimus-eluting stents (CYPHER stents) demonstrated remarkable efficacy in reducing restenosis rates in patients with coronary artery disease. There is a concern of sub-acute and late stent thrombosis. Tissue factor (TF) is critical in thrombosis. This study investigated the effect of sirolimus on TF expression and activity in cultured human vascular smooth muscle cells (SMCs). METHODS: SMCs were cultured from human saphenous veins and aortas. Quiescent cells were stimulated with sirolimus (0.1 – 20 ng/ml) over 24 hours. Cellular TF expression and activity released into culture medium were measured. The effect of sirolimus on activation of mammalian target of rapamycin (mTOR) was measured by phosphorylation of the substrate p70s6k at T389, and activation of RhoA was measured by pull-down assay. RESULTS: Sirolimus increased TF protein level in cultured human SMCs in a concentration and time-dependent manner (about 2-fold, p < 0.01) reaching maximal effect at 5 ng/ml. The stimulation of TF expression by sirolimus was associated with inhibition of basal activity of mTOR. No effects of sirolimus on RhoA or p38mapk activation that are positive regulators of TF in vascular wall cells were observed. The stimulation of TF expression by sirolimus (20 ng/ml) was prevented by the HMG-CoA reductase inhibitor fluvastatin (1 μmol/L). However, no increase in TF activity released from SMC into culture medium was observed after sirolimus treatment. CONCLUSION: Although sirolimus stimulates TF protein expression in human SMC associated with inhibition of mTOR, it does not enhance TF activity released from the cells, suggesting a relatively safe profile of CYPHER stents. The inhibition of TF expression by fluvastatin favors clinical use of statins in patients undergoing coronary stenting.
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spelling pubmed-11901662005-08-25 Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells Zhu, Shengsi Viswambharan, Hema Gajanayake, Thusitha Ming, Xiu-Fen Yang, Zhihong BMC Cardiovasc Disord Research Article BACKGROUND: Sirolimus-eluting stents (CYPHER stents) demonstrated remarkable efficacy in reducing restenosis rates in patients with coronary artery disease. There is a concern of sub-acute and late stent thrombosis. Tissue factor (TF) is critical in thrombosis. This study investigated the effect of sirolimus on TF expression and activity in cultured human vascular smooth muscle cells (SMCs). METHODS: SMCs were cultured from human saphenous veins and aortas. Quiescent cells were stimulated with sirolimus (0.1 – 20 ng/ml) over 24 hours. Cellular TF expression and activity released into culture medium were measured. The effect of sirolimus on activation of mammalian target of rapamycin (mTOR) was measured by phosphorylation of the substrate p70s6k at T389, and activation of RhoA was measured by pull-down assay. RESULTS: Sirolimus increased TF protein level in cultured human SMCs in a concentration and time-dependent manner (about 2-fold, p < 0.01) reaching maximal effect at 5 ng/ml. The stimulation of TF expression by sirolimus was associated with inhibition of basal activity of mTOR. No effects of sirolimus on RhoA or p38mapk activation that are positive regulators of TF in vascular wall cells were observed. The stimulation of TF expression by sirolimus (20 ng/ml) was prevented by the HMG-CoA reductase inhibitor fluvastatin (1 μmol/L). However, no increase in TF activity released from SMC into culture medium was observed after sirolimus treatment. CONCLUSION: Although sirolimus stimulates TF protein expression in human SMC associated with inhibition of mTOR, it does not enhance TF activity released from the cells, suggesting a relatively safe profile of CYPHER stents. The inhibition of TF expression by fluvastatin favors clinical use of statins in patients undergoing coronary stenting. BioMed Central 2005-07-15 /pmc/articles/PMC1190166/ /pubmed/16018822 http://dx.doi.org/10.1186/1471-2261-5-22 Text en Copyright © 2005 Zhu et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Zhu, Shengsi
Viswambharan, Hema
Gajanayake, Thusitha
Ming, Xiu-Fen
Yang, Zhihong
Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells
title Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells
title_full Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells
title_fullStr Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells
title_full_unstemmed Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells
title_short Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells
title_sort sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1190166/
https://www.ncbi.nlm.nih.gov/pubmed/16018822
http://dx.doi.org/10.1186/1471-2261-5-22
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