Grant: Operating Grant

Aging increases the risk to develop cardiovascular diseases such as coronary artery disease that leads to cardiac pain, dysfunction, and finally to cardiac arrest. Long before such an event, the vascular endothelium, a cell layer lining the inner surface of the arteries, has been dysfunctional. At first, this alteration is reversible, but with time and aging, it becomes irreversible and causes the development of atherosclerosis, a fat deposit that grows into the arteries of the heart, the coronaries, and induces CAD. The endothelium dilates the arteries and prevents blood clotting, permitting adequate blood flow, and prevents adhesion and infiltration of inflammatory cells that facilitate the growth of the atherosclerotic plaque. During the last term of CIHR support, we discovered a new protein, angiopoietin like-2 (angptl2). Angptl2 is highly expressed in the endothelium of patients with premature atherosclerosis. We reported that angptl2 is detectable in the blood from young adult mice, and that angptl2 increases in the blood with age and CAD, both in mice and in humans. We generated a mouse that does not produce angptl2 and found them to be resistant to the deleterious effects of a high-fat diet. We also produced a human form of angptl2 in the laboratory and showed that it stimulates the production of free radicals that damage the endothelium, induces inflammation and promotes atherosclerosis in mice. Furthermore, our data show that in patients with CAD, angptl2 levels are 6-fold higher in the blood compared to healthy subjects. Importantly, blood angptl2 levels decrease after a 3-month beneficial exercise-based lifestyle intervention in patients. In this project, we therefore propose that angptl2 is a biomarker predicting a dysfunctional endothelium, that it appears in the blood before the damage to the endothelium is irreversible and that angptl2 may contribute to the development of age-related atherosclerosis.