Grant: Project Grant

Background/Importance: Atherosclerosis or "hardening of the arteries" is the leading cause of death in Canada and worldwide. Accumulation of harmful cholesterol from LDL particles in blood vessels is the key reason for formation of the blockages or "plaques" that lead to heart attacks and strokes. A key enzyme called lysosomal acid lipase (LAL) is necessary to break down the cholesterol molecules from LDL so that cells can excrete this cholesterol and reduce the size of plaques. Goals/Research Aims: We recently reported that the type of cells accumulating the most cholesterol in arteries are smooth muscle cells (SMCs), not macrophages, a type of white blood cell attracted into the artery due to damage and inflammation, as long believed. While studying the reason SMCs accumulate the most cholesterol, we have made the original observation that they have a relatively low amount of LAL when compared to macrophages. We therefore want to test the possibility that low LAL in SMCs is the main reason these cells do not excrete their excess cholesterol, and that increasing the amount of LAL in SMCs is a novel way to reduce atherosclerosis. Approaches: To address this question we will 1) examine whether giving cells back LAL helps them to turn on the cholesterol removal pathway, 2) study human coronary arteries and aortas to confirm that SMCs in the plaques have low levels of LAL, 3) study whether mice, which also show most cholesterol in SMCs in the artery plaque, also have reduced LAL in SMCs and whether extra LAL corrects their ability to excrete cholesterol, and 4) study whether mice that have an increase in LAL specifically in their artery SMCs show less plaque development and increased ability to remove existing plaque. Expected Outcomes: Based on our strong initial data we expect these studies to show that low levels of LAL in artery SMCs is a major cause of plaque formation, and that supplementing LAL in the SMCs is a novel way to reduce heart attacks and strokes.