Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models
<p>Abstract</p> <p>Background</p> <p>Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is a rationally designed immunosuppressive drug. The current study investigates the effect of MMF on key pattern of restenosis in a cascade of in vitro and ex vivo...
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doaj-727e03ec69094a2ba0d06fa4aa24a7b02020-11-25T03:40:10ZengBMCBMC Cardiovascular Disorders1471-22612005-05-0151910.1186/1471-2261-5-9Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo modelsBaur Reginevon Müller LutzWeber Christian MKaspar VerenaViola SandraVoisard RainerGastrock-Balitsch IrisHombach Vinzenz<p>Abstract</p> <p>Background</p> <p>Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is a rationally designed immunosuppressive drug. The current study investigates the effect of MMF on key pattern of restenosis in a cascade of in vitro and ex vivo models.</p> <p>Methods</p> <p>Part I of the study investigated in northern blot and cytoflow studies the effect of MMF (50, 100, 150, 200, 250, and 300 μg/mL) on TNF-α induced expression of intercellular adhesion molecule 1 (ICAM-1) in human coronary endothelial cells (HCAEC) and human coronary medial smooth muscle cells (HCMSMC). Part II of the study applied a human coronary 3D model of leukocyte attack, the 3DLA-model. HCAEC and HCMSMC were cultured on both sides of a polycarbonate filters, mimicking the internal elastic membrane. Leukocyte attack (LA) was carried out by adding human monocytes (MC) on the endothelial side. The effect of MMF (50 μg/mL) on adhesion and chemotaxis (0.5, 1, 2, 3, 4, 6, and 24 h after LA) and the effect on proliferation of co-cultured HCMSMC (24 h after LA) was studied. In part III of the study a porcine coronary organ culture model of restenosis (POC-model) was used. After ex vivo ballooning MMF (50 μg/mL) was added to the cultures for a period of 1, 2, 3, 4, 5, 6, and 7 days. The effect on reactive cell proliferation and neointimal thickening was studied at day 7 and day 28 after ballooning.</p> <p>Results</p> <p>Expression of ICAM-1 in northern blot and cytoflow studies was neither clearly inhibited nor stimulated after administration of MMF in the clinical relevant concentration of 50 μg/mL. In the 3DLA-model 50 μg/mL of MMF caused a significant antiproliferative effect (p < 0.001) in co-cultured HCMSMC but had no effect on MC-adhesion and MC-chemotaxis. In the ex vivo POC-model neighter reactive cell proliferation at day 7 nor neointimal hyperplasia at day 28 were significantly inhibited by MMF (50 μg/mL).</p> <p>Conclusion</p> <p>Thus, the data demonstrate a significant antiproliferative effect of clinical relevant levels of MMF (50 μg/mL) in the 3DLA-model. The antiproliferative effect was a direct antiproliferative effect that was not triggered via reduced expression of ICAM-1 or via an inhibition of MC-adhesion and chemotaxis. Probably due to technical limitations (as e.g. the missing of perfusion) the antiproliferative effect of MMF (50 μg/mL) could not be reproduced in the coronary organ culture model. A cascade of focused in vitro and ex vivo models may help to gather informations on drug effects before large experimental studies are initiated.</p> http://www.biomedcentral.com/1471-2261/5/9 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Baur Regine von Müller Lutz Weber Christian M Kaspar Verena Viola Sandra Voisard Rainer Gastrock-Balitsch Iris Hombach Vinzenz |
spellingShingle |
Baur Regine von Müller Lutz Weber Christian M Kaspar Verena Viola Sandra Voisard Rainer Gastrock-Balitsch Iris Hombach Vinzenz Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models BMC Cardiovascular Disorders |
author_facet |
Baur Regine von Müller Lutz Weber Christian M Kaspar Verena Viola Sandra Voisard Rainer Gastrock-Balitsch Iris Hombach Vinzenz |
author_sort |
Baur Regine |
title |
Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models |
title_short |
Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models |
title_full |
Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models |
title_fullStr |
Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models |
title_full_unstemmed |
Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models |
title_sort |
effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models |
publisher |
BMC |
series |
BMC Cardiovascular Disorders |
issn |
1471-2261 |
publishDate |
2005-05-01 |
description |
<p>Abstract</p> <p>Background</p> <p>Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is a rationally designed immunosuppressive drug. The current study investigates the effect of MMF on key pattern of restenosis in a cascade of in vitro and ex vivo models.</p> <p>Methods</p> <p>Part I of the study investigated in northern blot and cytoflow studies the effect of MMF (50, 100, 150, 200, 250, and 300 μg/mL) on TNF-α induced expression of intercellular adhesion molecule 1 (ICAM-1) in human coronary endothelial cells (HCAEC) and human coronary medial smooth muscle cells (HCMSMC). Part II of the study applied a human coronary 3D model of leukocyte attack, the 3DLA-model. HCAEC and HCMSMC were cultured on both sides of a polycarbonate filters, mimicking the internal elastic membrane. Leukocyte attack (LA) was carried out by adding human monocytes (MC) on the endothelial side. The effect of MMF (50 μg/mL) on adhesion and chemotaxis (0.5, 1, 2, 3, 4, 6, and 24 h after LA) and the effect on proliferation of co-cultured HCMSMC (24 h after LA) was studied. In part III of the study a porcine coronary organ culture model of restenosis (POC-model) was used. After ex vivo ballooning MMF (50 μg/mL) was added to the cultures for a period of 1, 2, 3, 4, 5, 6, and 7 days. The effect on reactive cell proliferation and neointimal thickening was studied at day 7 and day 28 after ballooning.</p> <p>Results</p> <p>Expression of ICAM-1 in northern blot and cytoflow studies was neither clearly inhibited nor stimulated after administration of MMF in the clinical relevant concentration of 50 μg/mL. In the 3DLA-model 50 μg/mL of MMF caused a significant antiproliferative effect (p < 0.001) in co-cultured HCMSMC but had no effect on MC-adhesion and MC-chemotaxis. In the ex vivo POC-model neighter reactive cell proliferation at day 7 nor neointimal hyperplasia at day 28 were significantly inhibited by MMF (50 μg/mL).</p> <p>Conclusion</p> <p>Thus, the data demonstrate a significant antiproliferative effect of clinical relevant levels of MMF (50 μg/mL) in the 3DLA-model. The antiproliferative effect was a direct antiproliferative effect that was not triggered via reduced expression of ICAM-1 or via an inhibition of MC-adhesion and chemotaxis. Probably due to technical limitations (as e.g. the missing of perfusion) the antiproliferative effect of MMF (50 μg/mL) could not be reproduced in the coronary organ culture model. A cascade of focused in vitro and ex vivo models may help to gather informations on drug effects before large experimental studies are initiated.</p> |
url |
http://www.biomedcentral.com/1471-2261/5/9 |
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