Leiden University Scholarly Publications

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Kraaijeveld, A.O. (2009)

Identification of therapeutic targets in coronary artery disease: from patient to mice and back

Doctoral Thesis
The research described in this thesis consist of 2 parts: the first part involves studies on the influence of chemokines in cardiovascular disease. Chemokines are inflammatory proteins which play a pivotal role in atherosclerosis and myocardial ischemia. We identify 3 chemokines (CCL3, CCL5 and CCL18) whose levels are not only elevated during myocardial ischemia, but are also predictive of future cardiovascular events. Further studies focus on the individual role of CCL18 as well as CCL3 in atherogenesis and atherosclerotic plaque destabilization. The first is seen to recruit T-lymphocytes and the latter neutrophil granulocytes into the plaque, possibly augmenting plaque growth and destabilization. The second part focuses on the effect of gene modulation on vascular function. It start of with a study on the influence of aging in our atherosclerotic plaque mouse model. Additional genetic microarray revealed the Quaking gene as a possible modulator of atherosclerosis. This observation...Show moreThe research described in this thesis consist of 2 parts: the first part involves studies on the influence of chemokines in cardiovascular disease. Chemokines are inflammatory proteins which play a pivotal role in atherosclerosis and myocardial ischemia. We identify 3 chemokines (CCL3, CCL5 and CCL18) whose levels are not only elevated during myocardial ischemia, but are also predictive of future cardiovascular events. Further studies focus on the individual role of CCL18 as well as CCL3 in atherogenesis and atherosclerotic plaque destabilization. The first is seen to recruit T-lymphocytes and the latter neutrophil granulocytes into the plaque, possibly augmenting plaque growth and destabilization. The second part focuses on the effect of gene modulation on vascular function. It start of with a study on the influence of aging in our atherosclerotic plaque mouse model. Additional genetic microarray revealed the Quaking gene as a possible modulator of atherosclerosis. This observation is further explored in studies which show a link between Quaking genetic polymorphisms and an enhanced risk of developing in-stent restenosis following percutaneous coronary intervention. This is partly mediated by disturbed vascular smooth cell function. Finally, the MEF2 gene is studied for its role in myocardial infarction as genetic mutations in the MEF2A gene are associated with enhanced risk for a myocardial infarction. In a mouse model, we show that this is primarily due to decreased endothelial cell function, leading to plaque erosion.Show less
Acute coronary syndromes
Atherosclerosis
Chemokines
Gene therapy
Genetics
Plaqu rupture
Restenosis
All authors
Kraaijeveld, A.O.
Supervisor
Biessen, E.A.L.; Jukema, J.W.; Berkel, T.J.C. van
Qualification
Doctor (dr.)
Awarding Institution
Leiden University Medical Center (LUMC), Leiden University
Date
2009-10-01
ISBN (print)
9789085595588

Funding

Sponsorship
LACDR Dutch Heart Foundation JE Jurriaanse Stichting Maquet BV Boehringer Ingelheim BV Pfizer BV Schering-Plough BV Biotronik BV Daiichi Sankyo BV Eli Lilly BV Merck Sharp and Dome BV Novartis BV Astra-Zeneca BV