Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo modelsReport as inadecuate

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BMC Cardiovascular Disorders

, 5:9

First Online: 12 May 2005Received: 17 December 2004Accepted: 12 May 2005DOI: 10.1186-1471-2261-5-9

Cite this article as: Voisard, R., Viola, S., Kaspar, V. et al. BMC Cardiovasc Disord 2005 5: 9. doi:10.1186-1471-2261-5-9


BackgroundMycophenolate 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.

MethodsPart 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.

ResultsExpression 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.

ConclusionThus, 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.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2261-5-9 contains supplementary material, which is available to authorized users.

Sandra Viola, Verena Kaspar, Christian M Weber contributed equally to this work.

Author: Rainer Voisard - Sandra Viola - Verena Kaspar - Christian M Weber - Lutz von Müller - Regine Baur - Iris Gastrock-Balitsc

Source: https://link.springer.com/

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