Grant: Operating Grant

Atherosclerosis is the leading cause of death in Western societies. It is the most important cause of various heart diseases, strokes, myocardial infarctions, and even high blood pressure. Accumulation of excess cholesterol in macrophages (an important cell in atherosclerosis) is a key factor in the development of atherosclerosis. Current therapeutic strategies to prevent atherosclerosis are primarily based on the use of lipid-lowering drugs, statins, which decrease cholesterol synthesis and serum low-density lipoprotein (LDL) cholesterol levels (sometimes referred as the 'bad' cholesterol). The treatment of patients with statins reduces cardiovascular events by about 20 to 40% thereby indicating an important need for new therapies. Numerous studies have provided unquestionable evidence that plasma levels of high-density lipoprotein (HDL), sometimes referred as the 'good' cholesterol, are negatively associated with atherosclerosis. One of the most important roles of HDL in protection against atherosclerosis is the removal of cholesterol from macrophages. The initial and important step in HDL-mediated removal of cholesterol is the efflux of cholesterol from macrophages. There are two proteins that play an important role in this step which are the so-called ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1. Here we are investigating how these proteins help macrophages remove excessive cholesterol, such as do they pump cholesterol directly out from cells? Do they need other partners? We will conduct this research using state-of-the-art techniques in combination with several investigative approaches. With the help of other University of Alberta collaborators, we will gain deep insights into how ABC transporters mediate cholesterol efflux and how they help prevent atherosclerosis. The answers to these questions will provide the basis for the develpment of new drugs for the treatment of patients with increased risk of premature cardiovascular disease.