The studies described in this thesis focus on gene therapeutic strategies to target pathological vascular wall remodeling after PT(C)A or bypass surgery. Inflammatory processes and extracellular... Show moreThe studies described in this thesis focus on gene therapeutic strategies to target pathological vascular wall remodeling after PT(C)A or bypass surgery. Inflammatory processes and extracellular proteases, both activated by mechanical and vascular injury caused by these interventions, are thought to contribute largely to the development of post-angioplasty restenosis and vein graft disease. Therefore, viral and non-viral gene therapy techniques were used in these studies to deliver genes encoding protective as well as inhibiting proteins in order to modulate the inflammatory cascade (i.e. IL-10 and the MCP-1/CCR-2 pathway) in the first part of this thesis and the plasminogen activator and MMP-system in the second part. Finally, the expression of several involving genes was blocked locally by RNA interference techniques in the last part of this thesis. The possibilities and effects of these gene therapy applications were studied in cell cultures, in a human saphenous vein organ culture model and in two mouse models of restenosis and vein graft disease. Altogether, these studies provided more insight into the pathophysiology of post-interventional remodeling and several potential therapeutic strategies were assessed. Show less
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... 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
While currently available therapeutic options for the treatment of acute myocardial infarction are sufficient for the treatment of symptoms, the underlying causes usually remain unresolved, being... Show moreWhile currently available therapeutic options for the treatment of acute myocardial infarction are sufficient for the treatment of symptoms, the underlying causes usually remain unresolved, being loss of electrically active, contractile, myocardial tissue. Recently, extensive research has been performed in the field of cell and gene therapy. The ultimate aim of these therapies is to __heal__ the infarcted area on a more biological basis, by repopulating the damaged area with __new__ cells that contribute to proper cardiac function, including electrical activation of the myocardium. In order to comprehend the potential therapeutic value and hazard of cell modification and transplantation for ischemic heart diseases, one should consider the heart as a highly integrative, electromechanical organ. Therefore, the aim of this thesis was to explore, from a mechanistic and electrophysiological point of view, the integrative and functional aspects of cell modification and transplantation as therapeutic options to cure the damaged, ischemic heart. Show less
