14q32 Small Nucleolar RNAs in Cardiovascular Disease

Our research focuses on changes in the walls of our blood vessels during cardiovascular disease like myocardial infarction and peripheral arterial disease. These cardiovascular diseases are both caused by atherosclerosis. In atherosclerosis, cholesterol from the blood starts to accumulate inside the walls of important arteries. Inflammatory cells are then attracted to the vessel wall in order to clean up the mess. However, when they fail to breakdown the cholesterol, they change into what we call foam cells that remain stuck in the vessel wall. Slowly, this accumulation of cholesterol and foam cells grows into a plaque. If the plaque ruptures, this triggers the immediate formation of a blood clot, which blocks the flow of blood, and oxygen, to the heart or legs. But even stable plaques can cause complaints. As the plaque in the arterial grows, the artery itself becomes narrower, partially blocking the blood supply. When atherosclerosis causes health problems, invasive treatment, such as stent-placement or bypass-surgery, is necessary to restore the flow of blood and oxygen. Unfortunately, in many patients, the damage inflicted by these procedures leads to rapid re-occlusion of the artery, which is called restenosis. Our bodies have two ways of restoring blood flow. Angiogenesis is the process where many, tiny blood vessels sprout from existing ones and grow into the tissue that was deprived of oxygen. This way, the available blood is distributed more evenly throughout the body. Arteriogenesis is the process where small, pre-existing, connections between the blocked artery and a neighbouring artery become larger and, more importantly, wider. This way, these connections can ultimately form a natural bypass around the plaque. Unfortunately, in patients with cardiovascular disease, angiogenesis and arteriogenesis dont work as well as they should. On top of that, many factors that stimulate angiogenesis and arteriogenesis also stimulate atherosclerosis and restenosis. We discovered that a specific group of microRNAs and snoRNAs play a crucial role in all these changes in the wall of blood vessels. Both microRNAs and snoRNAs are small molecules that control many different processes in the body, by giving subtle hints to our cells. MicroRNAs and snoRNAs can very precisely regulate the activity of many of our genes at the same time, comparable to the director of an orchestra. Furthermore, we found that if we target the right microRNA or snoRNA with specific drugs, we can stimulate angiogenesis and arteriogenesis without stimulating atherosclerosis and restenosis. In this project, we will further investigate exactly how these microRNAs and snoRNAs work so that they may be used as future therapy for patients with cardiovascular disease.

Our research focuses on changes in the walls of our blood vessels during cardiovascular disease like myocardial infarction and peripheral arterial disease. These cardiovascular diseases are both caused by atherosclerosis. In atherosclerosis, cholesterol from the blood starts to accumulate inside the walls of important arteries. Inflammatory cells are then attracted to the vessel wall in order to 'clean up the mess'. However, when they fail to breakdown the cholesterol, they change into what we call 'foam cells' that remain stuck in the vessel wall. Slowly, this accumulation of cholesterol and foam cells grows into a plaque. If the plaque ruptures, this triggers the immediate formation of a blood clot, which blocks the flow of blood, and oxygen, to the heart or legs. But even stable plaques can cause complaints. As the plaque in the arterial grows, the artery itself becomes narrower, partially blocking the blood supply. When atherosclerosis causes health problems, invasive treatment, such as stent-placement or bypass-surgery, is necessary to restore the flow of blood and oxygen. Unfortunately, in many patients, the damage inflicted by these procedures leads to rapid re-occlusion of the artery, which is called 'restenosis'. Our bodies have two ways of restoring blood flow. 'Angiogenesis' is the process where many, tiny blood vessels sprout from existing ones and grow into the tissue that was deprived of oxygen. This way, the available blood is distributed more evenly throughout the body. 'Arteriogenesis' is the process where small, pre-existing, connections between the blocked artery and a neighbouring artery become larger and, more importantly, wider. This way, these connections can ultimately form a 'natural bypass' around the plaque. Unfortunately, in patients with cardiovascular disease, angiogenesis and arteriogenesis don't work as well as they should. On top of that, many factors that stimulate angiogenesis and arteriogenesis also stimulate atherosclerosis and restenosis. We discovered that a specific group of 'microRNAs' and 'snoRNAs' play a crucial role in all these changes in the wall of blood vessels. Both microRNAs and snoRNAs are small molecules that control many different processes in the body, by giving subtle hints to our cells. MicroRNAs and snoRNAs can very precisely regulate the activity of many of our genes at the same time, comparable to the director of an orchestra. Furthermore, we found that if we target the right microRNA or snoRNA with specific drugs, we can stimulate angiogenesis and arteriogenesis without stimulating atherosclerosis and restenosis. In this project, we have further investigated exactly how these microRNAs and snoRNAs work so that they may be used as future therapy for patients with cardiovascular disease.