Grant: CIHR Fellowship

Cardiovascular disease (CD) is the leading cause of death and illness in Canada. Atherosclerosis, also known as a hardening of arteries, is responsible for one in five cardiovascular-related deaths. Over the past 30 years, researchers have focused on the profound dynamic changes in vascular biology, especially in the endothelium, during atherosclerosis. Composed of endothelial cells, the endothelium provides a protective barrier between the blood and surrounding tissue. How endothelial cells regulate vascular homeostasis is not entirely known. Emerging evidence has indicated that autophagy is a major modulator of endothelial cell regulation and atherosclerosis. Autophagy refers to the process of degrading and recycling malfunctioning cellular components. It is activated as an adaptive response to stressful conditions. Interestingly, loss of autophagy has been implicated in the pathogenesis of diverse chronic diseases including neurodegenerative diseases, cancer, diabetes, inflammatory bowel disease and more recently atherosclerosis. We hypothesize that intact autophagy machinery plays an essential role in limiting inflammation-induced endothelial dysfunction and that loss of endothelial autophagy increases atherosclerosis. Accordingly, (i) endothelial-specific deletion of the essential autophagy gene ATG7 in mice will result in endothelial dysfunction, and endothelial inflammasome activation; and (ii) ATG7endo/ApoE-/- double knockout mice will develop increased atherosclerosis. Our aim is to determine how autophagy affects the progression of atherosclerosis. The long term objective of this research to increase our understanding of atherosclerosis in humans, and identify potential drug targets, allowing the development of pharmaceutical measures which can help us control the progression of atherosclerosis.