Bot, I.

Leiden University Scholary Publications

Modulation of Atherothrombotic Factors:  Novel Strategies for Plaque Stabilization Modulation of Atherothrombotic Factors:  Novel Strategies for Plaque Stabilization PROEFSCHRIFT ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van de Rector Magnificus Dr. D.D. Breimer, hoogleraar in de faculteit der W iskunde en Natuurwetenschappen en die der Geneeskunde, volgens besluit van het Colege voor Promoties te verdedigen op donderdag 22 september 2005 klokke 15.15 uur door Ilze Bot geboren te Dordrecht in 1977 Promotiecommissie Promotor:  Prof. dr. Th.J.C. van Berkel Copromotor:   Dr. E.A.L. Biessen Referent:  Prof. dr. C. Weber (Universitätsklinikum, Aachen) Overige leden:  Prof. dr. G.J. Mulder  Prof. dr. P.T. Kovanen (Wihuri Research Institute, Helsinki)  Prof. dr. M.J.A.P. Daemen (Universiteit Maastricht)  Dr. M.J. Smit (Vrije Universiteit, Amsterdam) The studies presented in this thesis were supported by grant 016.026.019 from the Netherlands Organization for Scientific Research (ZonMW) and were performed at the Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands. Financial support by the Netherlands Heart Foundation for the publication of this thesis is gratefully acknowledged. The printing of this thesis was financially supported by: - Leids Universiteits Fonds - LACDR - Dr. Ir. Van de Laar Stichting - J.E. Jurriaanse Stichting      Aan mijn ouders      aan Jan-W ilem         Cover:  Intraplaque hemorrhage in a collar-induced atherosclerotic lesion of an ApoE-/- mouse after activation of adventitial mast cells Printing: PrintPartners Ipskamp, Enschede, The Netherlands ISBN-10: 9090196390 ISBN-13: 9789090196398 Bot, Ilze Modulation of Atherothrombotic Factors: Novel Strategies for Plaque Stabilization  Proefschrift Leiden. Met literatuur opgave – Met samenvatting in het Nederlands © 2005 Ilze Bot No part of this thesis may be reproduced or transmitted in any form or by any means, without written permission of the author Contents                     PageChapter 1   General introduction         9Section 1: Matrix and Cell Homeostasis in Atherosclerotic Plaques    43 Chapter 2  Serine Protease Inhibitor Serp-1 Strongly Impairs     45 Atherosclerotic Lesion Formation and Induces a  Stable Plaque Phenotype in ApoE-/- Mice Chapter 3    Viral Cross-Class Serpin Inhibits Apoptosis,      61 Inflammation and AtherosclerosisChapter 4  Atherosclerotic Lesion Progression Changes     77 Lysophosphatidic Acid Homeostasis to Favor Its  AccumulationSection 2: Inflammation and Plaque Stabilization      89Chapter 5  Low Dose FK506 Blocks Collar-Induced       91 Atherosclerotic Plaque Development and Stabilizes  Plaques in ApoE-/-Mice Chapter 6 Adventitial Mast Cell Activation Causes    109 Atherosclerotic Plaque Destabilization in ApoE-/- miceChapter 7 Lentiviral ShRNA Silencing of Murine Bone Marrow  127 Cell CCR2 Leads to Persistent Knockdown of CCR2  Function in vivoChapter 8 General Discussion and Perspectives   145 Summary        163 Nederlandse Samenvatting      167 Abbreviations        172 Publications        174 Curriculum Vitae        175 

Modulation of Atherothrombotic Factors: Novel Strategies for Plaque Stabilization

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Modulation of Atherothrombotic Factors: Novel Strategies for Plaque Stabilization

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