Grant: Project Grant

Heart attacks, heart failure and stroke combined are a leading cause of reduced quality of life and death in Canada, and are caused primarily by the buildup of plaque in arteries in a disease called atherosclerosis. While it was previously thought that a type of white blood cell called macrophages are the main cells where cholesterol accumulates in arteries to form plaque, we found that in both humans and mice, the biggest contributor to cholesterol overloaded cells are artery smooth muscle cells (SMCs), which are the main cell type in the plaque. We further discovered several reasons cholesterol accumulates in SMCs that are not present in macrophages. In the proposed research, we will determine the relevance of cholesterol-overloaded SMCs to both the accumulation and removal of plaque from arteries. To do this, we will explore the gene expression patterns of human coronary artery SMCs to understand if cholesterol overload represents a harmful or possibly protective condition in these cells. Using diseased human hearts removed at the time of heart transplant, we will determine how previous treatment with cholesterol-lowering medications or not affects the number and characteristics of cholesterol-overloaded SMCs and macrophages in coronary arteries, with our idea being that SMC foam cells resist removal by these medications. We will also determine whether normal or plaque SMCs affect the tendency of macrophages to become cholesterol overloaded, and whether inflammatory or repair macrophages turn on cholesterol accumulation in SMCs. Through this research, we will be able to demonstrate whether SMCs in arteries represent a unique and currently untapped target to intervene with new treatments to reduce heart attack, heart failure and stroke beyond what currently available treatments can do. The ultimate goal is to increase disease-free years of life for Canadians and people worldwide.