Grant: Doctoral: Vanier Canada Graduate Scholarships

Cardiovascular diseases remain the leading cause of death worldwide. In Canada, more than 70,000 people die yearly from these conditions, and more than $18 billion is spent on disease management annually. Atherosclerosis, the underlying disease of many cardiovascular disorders, is characterized by the formation of a cholesterol rich plaque on the artery wall. Development of an unstable plaque may result in sudden rupture, which can lead to death due to heart attack or stroke. Present treatment focuses on managing risk factors such as elevated blood cholesterol levels. However, mortality due to cardiovascular diseases continues to rise, emphasizing the need for research into new therapeutical approaches. Granzyme B (GrB), a key enzyme that is released by immune cells, may promote atherosclerotic plaque instability by inducing arterial cell death and by degrading extracellular proteins in the vessel wall. GrB is abundant in advanced atherosclerotic plaques and elevated blood levels of this enzyme are evident in patients who experience an acute heart attack. It is therefore possible that inhibition of GrB will be a valuable treatment approach in preventing the development and/or rupture of unstable atherosclerotic lesions. Protease inhibitor-9 (PI-9), the endogenous inhibitor of GrB in humans, is highly expressed in normal arteries, however its levels are reduced in arteries with atherosclerotic lesions. We hypothesize that a reduction in PI-9 expression may increase the vulnerability of the arterial wall to GrB-induced insult. The purpose of this study is to explore the role of PI-9 during atherosclerotic lesion development. Specifically, we will examine whether administration and/or increased expression of PI-9 can protect vascular cells against GrB activity. This investigation will allow us to evaluate the effectiveness of PI-9 as a potential therapeutic candidate for attenuating plaque instability and preventing sudden rupture.