The role of AMP-activated protein kinase (AMPK) in cardiovascular disease

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Fullerton, Morgan (Biochemistry, Microbiology and Immunology, University of Ottawa)
Mentor: McPherson, Ruth
Network Affiliation: Canadian Vascular Network
1. The health problem/issue
Heart disease is a condition that affects more than one million Canadians, and costs the Canadian healthcare system almost 21 billion dollars annually. Atherosclerosis is the buildup of cholesterol and immune cells in the lining of the arteries (atherosclerotic plaque), and is a leading cause of heart attack and stroke. In addition to risk factors such as obesity and type 2 diabetes, the way that our body handles the build up of cholesterol in the arteries is also very important in atherosclerosis. Specialized immune cells called macrophages are able to take up and store excess cholesterol, protecting the artery wall in the process. These macrophages have specialized pathways to then transfer the cholesterol to the circulating lipoprotein “HDL”, which then carries the cholesterol to the liver, where it can be safely removed (this is why HDL-cholesterol is called the “good” cholesterol). This is known as reverse cholesterol transport. However, when this process is overwhelmed, cholesterol builds in macrophages, turning them into macrophage foam cells and causing atherosclerosis to progress. Promotion of reverse cholesterol transport favours plaques to actually regress (shrink), which could be extremely helpful as a therapy. We have discovered that an important metabolic regulator called AMPactivated protein kinase (AMPK), activates reverse cholesterol transport in macrophages, but how this might impact atherosclerosis regression and cardiovascular disease is still unknown.
2. The objectives
We know that AMPK activation causes a beneficial removal of cholesterol from macrophage foam cells, but this important protein is a regulator of many important processes in the cell. The first objective of this proposal is to determine the overall role of AMPK in the regression of atherosclersosis in mice. The second objective will be to determine if AMPK activity in circulating immune cells can be used as a biomarker for cardiovascular risk in humans.
3. The approach
HeTo test our hypotheses we will use mice that have AMPK knocked out 1) in all cells or 2) only in macrophages. These mice will be fed a diet that will cause atherosclerosis. We will monitor these mice and perform therapeutic interventions with an AMPK-specific activator. We will also measure the amount and activity of AMPK in circulating immune cells (which are important for processing lipids and contribute to atherosclersosis).
4. The unique factors
This research will use a unique genetically engineered mouse model and proposes an innovative translation approach, such that we will test if AMPK measurments in human immune cells found in the blood) can give us an indiction of cardiovascular disease risk.
5. How the project is relevant to the objectives of the initiative
This research will use a unique genetically engineered mouse model and proposes an innovative translation approach, such that we will testHeart disease is the number one cause of death in Canada and costs tens of billions of dollars to our healthcare system. Atherosclerosis is a precursor to heart disease and has a number of risk factors such as diet, smoking and genetics. Although atherosclerosis progresses to heart disease, the beginning stages of this disease are very tightly linked to the amount of cholesterol that macrophage cells are exposed to. Our proposed research aims to better understand the pathways that control atherosclerotic plaque and its regression. By understanding and investigating ways that can better return cholesterol from macrophages in the arteries, to liver cells, we stand a better chance of slowing and
possibly reversing atherosclerosis. If AMPK measurments in human immune cells (found in the blood) can give us an indiction of cardiovascular disease risk.
6. The impact
We are proposing research that aims to understand the regression of atherosclerosis and slowing the progression to heart disease, which affects more than a third of Canadians. By understanding the mechanisms by which AMPK controls cholesterol metabolism and how thisaffects atherosclerosis,we are better positioned to uncover novel mechanisms that contribute to atherosclerosis and heart disease, and more importantly, prevent/treat it. Our hope is that this leads to the development of more effective prevention and therapeutic strategies. This would help to reduce the tremendous burden that heart disease places on Canadians.