The work described in this thesis was aimed at identifying the role of cell cycle and apoptosis genes in atherosclerosis. Atherosclerosis is the primary cause of cardiovascular disease, a disorder... Show moreThe work described in this thesis was aimed at identifying the role of cell cycle and apoptosis genes in atherosclerosis. Atherosclerosis is the primary cause of cardiovascular disease, a disorder occurring in the large and medium-sized arteries of the body. Although in the beginning 90s promising lipid lowering therapies predicted a strong reduction in cardiovascular deaths, in westernized societies it is still the underlying cause of about 40% of all deaths, indicating that treatment of atherosclerosis goes beyond lipid lowering solely. In addition to lipids, continuous cell growth (cell cycle) and cell death (i.e. apoptosis and necrosis) processes play a central role in the development of atherosclerosis. To investigate the role of several cell cycle and apoptosis genes (i.e. p53, Rb and Mdm2) in atherosclerosis we generated and characterized several mouse models based on site-specific recombinase (SSR) technology. The studies described in this thesis show that next to therapies aiming at lifestyle interventions, lipid therapies and regulation of inflammation, targeting cell cycle and apoptosis genes on lesional or cellular level might prove the most effective way to reduce the burden of atherosclerosis. Show less
The heart is built for life-long uninterrupted function, supporting blood flow through the organism. During life, the organism as well as its organs will become challenged by exogenous and... Show moreThe heart is built for life-long uninterrupted function, supporting blood flow through the organism. During life, the organism as well as its organs will become challenged by exogenous and endogenous stresses that should be coped with. To be able to adapt to stresses such as altered loading conditions, changes in myocardial perfusion and exposure to toxic agents, the heart possesses ample capabilities. This thesis deals with the question how cardiac cells react to different stresses in an attempt to adapt to the new circumstances. The effect of mechanical stress as well as integrin stimulation on cardiac cells was examined and described. Besides we investigated the reaction of cardiac cells to DNA damage caused by either ionizing radiation or UV-irradiation. The studies reported in this thesis confirm that cardiac cells, both myocytes and fibroblasts have the capacity to respond adequately to exogenous stresses. The responses that have been studied in detail demonstrate that these cells possess systems that sense the stress, transmit its message to the cell interior, and alter gene expression, leading to appropriate reactions. Show less
